Clinical trial NCT01588431
Conditions: Carcinoma, Squamous Cell of Head and Neck
Keywords: Locally advanced head and neck cancer Squamous cell carcinoma of the head and neck
Sponsor: The University of Texas Health Science Center at San Antonio
Start date: 2011-12-01; Completion date: 2022-10-04
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) is treated with various combinations of radiation and chemotherapy. This study aims to evaluate the rate of complete responses with induction therapy (primary endpoint) and progression-free survival, overall survival and objective response rates of docetaxel, cisplatin, cetuximab, and bevacizumab (TPE-A) followed by radiation therapy, cisplatin, cetuximab, and bevacizumab (XPE-A). Also, the investigators plan to investigate a panel of EGFR and angiogenesis biomarkers in pre-and post- treatment tumor biopsies. Finally, the investigators will evaluate the associated treatment toxicities and the quality of life.

Detailed description:
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) is treated with various combinations of radiation and chemotherapy. Docetaxel and cisplatin have been combined in Phase II trials in recurrent or metastatic head and neck cancer with very encouraging results. Induction therapy with docetaxel/cisplatin followed by chemoradiotherapy was investigated in a randomized Phase II study in nasopharyngeal cancer and showed superior PFS and OS in comparison with chemoradiation alone. Cetuximab is a chimerized EGFR monoclonal antibody that has produced positive results in Phase III trials in combination with either radiation for locally advanced disease or chemotherapy for metastatic disease. Upregulation of vascular endothelial growth factor (VEGF) has been associated with cetuximab resistance. Bevacizumab, an anti-VEGF antibody is currently being investigated in SCCHN with promising results. The investigators have previously shown that cisplatin, docetaxel and cetuximab (TPE) followed by radiotherapy, cisplatin and cetuximab (XPE) is feasible and highly efficacious in locally advanced SCCHN (Argiris, A. et al.JCO 2011). In this Phase II study the investigators evaluate the addition of bevacizumab to induction therapy with TPE (TPE-A) and to subsequent XPE (XPE-A).

Specific aims:

To evaluate the rate of complete responses with induction therapy (primary endpoint) and progression-free survival, overall survival and objective response rates. Also, the investigators plan to investigate a panel of EGFR and angiogenesis biomarkers in pre- and post- treatment tumor biopsies. Finally, the investigators will evaluate the associated treatment toxicities and the quality of life.

Subject population:

The investigators will enroll patients with previously untreated locally advanced SCCHN (see detailed eligibility criteria).

Treatment plan:

Induction therapy consists of 3 cycles of bevacizumab 15mg/kg on day 1, docetaxel 75mg/m2 on day 1, loading dose of cetuximab 400mg/m2 on cycle 1, day 1, then 250 mg/m2 on all subsequent administrations (Day 8 and 15 of cycle 1 and days 1,8,15 of cycles 2 and 3), cisplatin 75mg/m2 on day 1, docetaxel 75mg/m2 on day 1, repeated every 21 days. After 3 cycles of induction therapy, patients will receive standard radiation 70-74 Gy/ 200 cGy/ daily, 5 days/ week with concurrent weekly cisplatin 30mg/m2, cetuximab 250mg/m2 and bevacizumab 15mg/kg every 3 weeks x 3. There is optional surgery for non-responders in the primary (stable disease) after TPE-A.

Statistical design and sample size:

Phase II, two-stage study with complete response rate after induction therapy as the primary endpoint. The sample size is 33 patients.

Arms: arm 1: Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, Cisplatin, Cetuximab and Bevacizumab (XPE-A), surgery
Interventions: intervention 1: Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, Cisplatin, Cetuximab and Bevacizumab (XPE-A), surgery
Intervention descriptions: intervention 1: Induction therapy consists of 3 cycles of bevacizumab 15mg/kg on day 1, cetuximab weekly days 1,8,15 (loading dose of cetuximab 400mg/m2 on cycle 1, day 1, then 250 mg/m2 on all subsequent administrations), cisplatin 75mg/m2 on day 1, docetaxel 75mg/m2 on day 1, repeated every 21 days. After 3 cycles of induction therapy, patients will receive standard radiation 70-74 Gy/ 200 cGy/ daily, 5 days/ week with concurrent weekly cisplatin 30mg/m2, cetuximab 250mg/m2 and bevacizumab 15mg/kg every 3 weeks x 3. There is optional surgery for non-responders in the primary (stable disease) after TPE-A.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
Official Study Title: A Phase II Study of Induction Docetaxel, Cisplatin, 
Cetuximab and Bevacizumab (TPE-A) Followed by Concurrent Radiation, 
Cisplatin, Cetuximab and Bevacizumab (XPE-A) in Patients with Locally 
Advanced Head and Neck Cancer (CTRC# 11-36) 
 
 
NCT number: NCT 01588431 
 
 
IRB Approval Date: 11-02-2016 
 
 
Unique Protocol ID: CTRC 11-36 


Page 1 of 3 
 
STOP 
NOT IRB 
APPROVED 
CCTTRRCC## 1111--3366 
 
 
Protocol Changes for the Revised Protocol dated October 25, 2016 for the study: A Phase II 
Study of Induction Docetaxel, Cisplatin, Cetuximab and Bevacizumab (TPE-A) Followed by 
Concurrent Radiation, Cisplatin, Ceh1ximab and Bevacizumab (XPE-A) in Patients with Locally 
Advanced Head and Neck Cancer (CTRC# 11-36) 
 
PREVIOUSLY READ: 
Cover Page, date of pr-
oto-
co-
l --------------- 
VERSION DATE: 
 
 
 
 
 
 
 
 
NOW READS: 
VERSION DATE: 
01 June 2011 
August 22, 2011 
Janua1y 4, 2012 
April 25, 2012 
November 2, 2012 
December 19, 2012 
March 25, 2013 
May 28, 2013 
December 5, 2013 
Janua1y 14, 2015 
 
 
01 June 2011 
August 22, 2011 
Janua1y 4, 2012 
April 25, 2012 
November 2, 2012 
December 19, 2012 
March 25, 2013 
May 28, 2013 
Janua1y 14, 2015 
October 25, 2016 
RECEIVED 
BByy Reegulatory AAffffaaiirrss aatt 22::4444ppmm,, OOcctt 2255,, 22001166 
 
 
 
 
 
 
RATIONALE:   Updated the version date of protocol. 
 
PREVIOUSLY READ: 
Header, entire protocol 
Janua1y 14, 2016 
 
NOW READS: 
RATIONALE: 
October 252 2016 
Updated the date of protocol 
PREVIOUSLY READ: Cover Page, Principal Investigator 
 
Woondong Jeong, MD 
Professor of Medicine 
UT Health Science Center at San Antonio 
Cancer Therapy & Research Center 
7979 Wurzbach Road MC8232 
Zeller Building- 4th Floor, Room Z4l 8 


Page 2 of 3 
 
San Antonio, TX 78229 
 
E-mail: jeongw@uthscsa.edu 
Phone number: 210-450-5956 
Fax number: 210-692-7502 
 
 
NOW READS: 
 
Anand Kamad, MD 
Professor of Medicine 
UT Health Science Center at San Antonio 
Cancer Therapy & Research Center 
7979 Wurzbach Road MC8232 
Zeller Building- 4th Floor, Room Z4l 8 
San Antonio, TX 78229 
 
E-mail: kamad@uthscsa.edu 
Phone number: 210-450-1267 
Fax number: 210-450-0417 
 
RATIONALE: Update p1incipal investigator information 
 
 
PREVIOUSLY READ: Page 37 
 
This is an investigator-initiated study. The principal investigator, Woondong Jeon, g 
 
 
MD, who 
may also sometin1es be refen ed to as the sponsor-investigator, is conducting the study and acting 
as the sponsor. 
 
NOW READS: 
 
This is an investigator-initiated study. The principal investigator, Anand Karnad, MD, who 
may also sometimes be refen ed to as the sponsor-investigator, is conducting the study and acting 
as the sponsor. 
 
RATIONALE: Update principal investigator info1mation 
 
 
 
PREVIOUSLY READ: Page 41 
 
For questions regarding the eligibility of subjects, Woondong Jeong, MD, should be contacted 
at (210) 450-5956. 
 
NOW READS: 
 
For questions regarding the eligibility of subjects, Anand Karnad, MD, should be contacted at 
(210) 450-1267. 


Page 3 of 3 
 
RATIONALE: Update principal investigator information 


CONFDI ENTIAL 
 
CCTTRRCC## 1111--3366 
 
 
 
 
 
PROT OCOL NUMBER: 
PROTOCOL TITL E: 
 
 
 
VERSION DATE: 
CTRC #11-36 
 
A Phase II Study of Induction Docetaxel, Cisplatin, Cetuximab and 
Bevacizumab (TPE-A) Followed by Conctm ent Radiation, Cisplatin, 
Cetuximab and Bevaciz umab (XPE-A) in Patients with Locally 
Advanced Head and Neck Cancer 
 
01 June 2011 
August 22, 2011 
Janmuy 4, 2012 
April 25, 2012 
November 2, 2012 
December 19, 2012 
March 25, 2013 
May 28, 2013 
December 5, 2013 
Januaiy 14, 2015 
October 25, 2016 
 
PRINCIPAL INVESTIGATOR: 
Anand Kam ad, MD 
Professor of Medicine 
UT Health Science Center at San Antonio 
Cancer Therapy & Research Center 
7979 Wurzbach Road MC8232 
Zeller Building-4th Floor, Room Z4l 8 
San Antonio, TX 78229 
 
E-mail: kainad@uthscsa.edu 
Phone number: 210-450-1267 
Fax number: 210-450-0417 
 
BIOSTATISTICIAN: 
Bradley Pollock, PhD 
UT Health Science Center at San Antonio 
Depaitment of Epidemiology and Biostatistics MC 7933 
7703 Floyd Curl Drive 
Admin Building, 3rd Floor, Room 314 
San Antonio, TX 78229 
 
E-mail: BPollock@uthscsa.edu 
Phone number: 210-567-0836 
Fax number: 210-567-0921 
 
CO-I NVESTI GATORS: 
See FDA 1572 
RECEIVED 
BByy Reegguullaattoorryy AAffffaaiirs at 2::4422 pmm,, OOcctt 25, 22001166 


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TABLEOFCONTENTS 
RESEARCH STUDY ABSTRACT ..................................................................................................................... 4 
STUDY SCHEMA .................................................................................................................................................... 5 
1 
BACKGROUND AND RATIONALE....................................................................................................................................... 6 
1.1 
Head and Neck Cancer. ........................................................................................................... 6 
1.2 
Chemotherapy for LocoregionallyAdvanced Disease ....................................................................... 6 
1.3 
CombinedModailty Therapyfor OrganPreservation .................................................................................................... 6 
1.4 
ConcomitantChemoradiotherapy  ................................................................................................. 7 
1.5 
RadiationplusCisplatin for Locally Advanced Head and Neck Cancer ................................................................ 7 
1.6 
InductionChemotherapy  ............................................................................................................. 9 
1.7 
Cisplatinand Docetaxel  ............................................................................................................... 9 
1.8 
Epidermal Growth Factor Recepto(rEGFR) and Cetuximab ................................................................................. 10 
1.9 
InductionChemotherapyFollowed by Chemoraidotherapy  ............................................................... 18 
1.1O   BevacizumabClinical Experience  ................................................................................................ 19 
1.11 BevacizumabStudies in Head and Neck Carcinoma at the University of Pittsburgh  ............................. 25 
1.12 Study Rationale........................................................................................................................................................ 25 
2 
OBJECTIVES ...................................................................................................................................................................................................... 26 
2.1 
Primary ....................................................................................................................................................................... 26 
2.2 
Secondray ........................................................................................................................................................................... 26 
3 
STUDYDESIGN ...................................................................................................................................................................................... 26 
3.1 
InductionTherapy (TPE-A) ...................................................................................................................................................... 26 
3.2 
ConcurentRadiotherapy,Cisplatin, Cetuximaband Bevaczi umab(XPE-A)  ........................................ 28 
3.3 
RadiationTherapy ..................................................................................................................................... 29 
3.4 
Supportive Care  ........................................................................................................................ 34 
3.5 
Gastrotsomy Tubes  .................................................................................................................... 34 
4 
SAFETY REPORTING OF ADVERSE EVENTS ................................................................................... 35 
4.1 
Definitions ......................................................................................................................................................... 35 
4.2 
Reporting to IRB ...................................................................................................................................... 38 
5 
STUDYSUBJECTS ............................................................................................................................................................ 39 
5.1 
Eligibility Criteria ............................................................................................................................................... 39 
5.2 
ExclusionCriteria ....................................................................................................................................................... 40 
6 
PATIENTREGISTRATION  .................................................................................................................. 41 
7 
DOSE MODIFICATIONS- InductionDocetaxel / Cisplatin/ Cetuximab / Bevacizumab(TPE-A)  ..................... 41 
7.1 
HematologicToxicity (Docetaxel) .................................................................................................................................... 41 
7.2 
Neurologic Toxicity (Docetaxel, Cisplaitn)  ...................................................................................... 43 
7.3 
Ototoxicity (Cisplaitn) ................................................................................................................................................ 43 
7.4 
Gastrointestinal Toxicity (Docetaxel, Cisplatin)  ............................................................................... 43 
7.5 
Renal Toxicity (Cisplatin) ........................................................................................................................................ 43 
7.6 
Hepatic Toxicity (Docetaxel) ...........................................................................................................................................44 
7.7 
Hypersentsiviity Reactions (Docetaxle)  .......................................................................................... 45 
7.8 
Fluid Retention(Docetaxel)  ......................................................................................................... 45 
7.9 
Other Non-HematologicToxicities  ............................................................................................... 45 
8 
DOSE MODIFICATOI NS- Radiation plusCisplatin / Cetuximab/ Bevaczi umab(XPE-A)  .............................. 45 
8.2 
Managementof CetuximabAdverseReactionsand Dose Modfiications ..........................................................49 
8.3 
BevacizumabDose Modfiicationand Toxicity Management. .......................................................... 52 
8.4 
Docetaxel-AssociatedHypersenstivity Reactions ............................................................................................................ 54 
8.5 
Fluid RetentionSyndrome ............................................................................................................................... 55 
8.6 
Hyperlarcimation ..................................................................................................................................................................................... 56 


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9 
DURATIONOF THERAPY/ WITHDRAWAL FROM STUDY ............................................................... 56 
10 
DRUG FORMULATIONAND PROCUREMENT  ................................................................................ 56 
10.1 Docetaxe.l ........................................................................................................................................................................... 56 
10.2 Cisplafin (Cis-diaminedichloroplatinu,mCDDP)  .............................................................................. 62 
10.3 Carboplatin  ...............................................................................................................................63 
10.4 Cetuximab(C225, ERBITUX)  ..................................................................................................... 65 
10.5 Bevacizumab  ...........................................................................................................................66 
11 
CLINICALAND LABORATORY EVALUATIONS ................................................................................................................. 69 
11.1 Evaluationsat Screening/ Baseline ..............................................................................................................................69 
11.2 EvaluationDuringTream
t ent  ....................................................................................................... 70 
11.3 Evaluationsat FollowUp ............................................................................................................................. 71 
12 
SUBJECTDISCONTINUAITON ................................................................................................................................................ 74 
13 
STATISTICALMETHODS ........................................................................................................................................................... 74 
13.1 Sample Size ........................................................................................................................................................................................... 74 
13.2 Analyses .................................................................................................................................................................... 75 
13.3 Defintiionof response  ................................................................................................................ 75 
14 
CORRELATIVESTUDIES  ............................................................................................................. 76 
14.1 Background and Methods ..................................................................................................... 76 
14.2 Material Submission ............................................................................................................................................................................. 76 
14.3 Banking ................................................................................................................................. 77 
14.4 BloodCorrelativesfor LavendeTr op and SerumRed Top Tubes  ...................................................... 77 
14.5 Methods ..................................................................................................................................................................................................... 77 
14.6 Shipping ..................................................................................................................................................................................................... 78 
15 
DATA SAFETY MONITORING ............................................................................................................................. 79 
16 
RETENTIONOF RECORDS ...................................................................................................... 83 
17 
REFERENCES ........................................................................................................................ 84 
APPENDIX A: ECOG Performance Status............................................................................................ 91 
APP ENDIX B: Procedurefor Obtaining a Urine Protein / Creatinine Ratio.................................... 92 
APPENDIXC: NCI Common Toxicity Criteria (CTCAE v 4.0) ............................................................ 93 
APPENDIX D: FDA MedWatch 3500a Form ......................................................................................... 94 
APPENDIX E: New York Heart Association (NYHA) Guidelines ......................................................... 95 
APPENDIX F: FACT - H&N ............................................................................................................................... 96 
APPENDIX G: AJCC Staging System, 7th Edition ................................................................................ 100 
APPEN DIX H: Gene ntech Safety Reporting Fax Cover Sheet. ............................................................ 114 


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Background 
RESEARCH STUDY ABSTRACT 
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) is ti-eated with vaiious 
combinations of radiation and chemotherapy. Docetaxel and cisplatin have been combined in Phase II 
trials in recun ent or metastatic head and neck cancer with very encoura ging re sults. Induct ion therapy 
with docetaxel/ci splatin followed by chemoradiotherapy was investigated in a randomized Phase II study 
in nasophaiyngeal cancer and showed superior PFS and OS in compa1i son with chemoradiation alone. 
Cetuximab is a chimerized EGFR monoclonal antibody that has produced positive results in Phase III 
trials in combination with either radiation for locally advanced disease or chemotherapy for metastatic 
disease. Upregulation of vasculai·endothelial growth factor (VEGF) has been associated with cetuximab 
resistance. Bevacizumab, an anti-VEGF antibody is cutTently being investiga ted in SCCHN with 
promising results. Two trials of bevacizumab-based regimens ai·e being conducted at UPMC (UPCI 
05-002 and UPCI 05-087) with ve1y promising results. We have previously shown that cisplatin, 
docetaxel and cetuximab (TPE) followed by radiotherapy, cisplatin and cetuximab (XPE) is feasible and 
highly efficacious in locally advanced SCCHN (UPCI 05-003, presented at ASCO 2008). In this Phase II 
study we evaluate the addition ofbevacizumab to induction therapy with TPE (TPE-A) and to subsequent 
XPE (XPE-A). 
Specific aims 
To evaluate the rate of complete responses with induction therapy (primaiy endpoint) and progression- 
free survival, overall survival and objective response rates. Also, we plan to investigate a panel of EGFR 
and angiogenesis biomarkers in pre- and post- tt·eatment tutnor biopsies. Finally, we will evaluate the 
associated treatment toxicities and the quality ofl ife. 
Subject population 
We will emoll patients with previously untreated locally advanced SCCHN (see detailed eligibility 
criteria). 
Treatment plan 
Induction therapy consists of 3 cycles of bevacizumab 15mg/kgon day 1, cetuximab weekly days 1, 8, 15 
(loading dose of cetuximab 400mg/m2 on cycle 1, day 1, then 250 mg/m2  on all subsequent 
administt·ation)s, cisplatin 75mg/m2 on day 1,  docetaxel 75mg/m2 on day  1, repeated eve1y 21 days. After 
3 cycles of induction therapy, patients will receive standard radiation 70-74 Gy/ 200 cGy/ daily, 5 days/ 
week with concmTent weekly cisplatin 30mg/m2, cetuximab 250mg/m2 and bevacizumab 15mg/kg eve1y 
3 weeks x 3. There is optional smge1y for non-responders in the primaiy (stable disease) after TPE-A. 
Statistical design and sample size 
Phase II, two-stage study with complete response rate after induction therapy as the p1imaiy endpoint. 
The sainple size is 33 patients. 


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CONFIDENTIAL 
 
 
*Selected patients who undergo complete resection will receive postoperative doses up to 66 Gy 
• 
HPV testing for all patients. Patients who are HPV positive or pl6 positive and have smoking histmy 
:::;10 pack-years are not eligible. Tumor biopsies at baseline (optional) and on cycle 1, day 21 
(plus/minus 2 days) (optional) 
• 
Blood samples at baseline (mandatory), after cycle 1 (before staiting cycle 2) and after cycle 3 of 
induction therapy (the week prior to staiting radiation,)8 weeks after completion of radiation and at six 
months after completion of radiation therapy. 
• 
G-CSF prophylaxis during induction (recommended), Neulasta on day 2 or Neupogen on days 2-11, or 
ciprofloxacin 500 mg BID days 5-14. 
• 
PET/CT at baseline, after 3rd cycle (before start ofradiation) and 8 weeks after RT completion 
*after loading dose of 400 mg/m2 
R 
Every 21 daysx 3cycles 
E 
PS 0-1  
Cis platin 
75 mglm2, day 1 
T 
! 
_,. 
Cetuximab 250 mg/rn2 days1,8,15• 
-+ 
s 
I 
111-I VB 
SCCHN 
Docetaxel 75mglm2, day1 
G 
Stage 
Bevacizumab 15mg/Kg day 1 
R 
 
 
E 
Radia tion x 7-8 weeks (70-74Gy)* 
Bevacizumab15 mg/Kg Q 3w 
Cetuximab 250 mg/m2 weekly 
Cis platin 30 mg/rn2 weekly 
Response assessment by PET/CT. 
Surgery for patientswith stable disease in primary 
tumor (optional) 
 
 
STUDY SCHEMA 
 
 
 


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1 
BACKGROUNDAND RATIONALE 
 
1.1 
Head and Neck Cancer 
More than 45,000 new cases of head and neck cancer are diagnosed annually in the United States1. Of 
these patients, two-thirds present with locoregionally advanced disease (AJCC stage III or IV) and one- 
third with early stage disease (AJCC stage I or II) . At presentation 10% of patients may be found to have 
involvementof distant organs, most commonly the lung. In addition, 20% of patients will develop 
clinically detected distant metastases over the course of their disease. In autopsy series up to 50% of 
patients with head and neck cancer are found to have metastases2•3. Approximately 90% of all head and 
neck malignancies are squamous cell carcinomas. The vast majority of head and neck malignancies can 
be attributed to the use of tobacco and alcohol. Human Papillomavirns has been implicated in a 
significant portion of oropharyngeal squamous cell carcinomas75 77. Due to their frequent histo1y of 
exposure to tobacco and alcohol patients with head and neck cancer are in high risk for other 
comorbidities associated with tobacco and alcohol, such as corona1y aite1y disease, chronic obstrnctive 
pulmona1ydisease, and liver disease4. In addition, they ai·e at high 1isk for the development of second 
primaiy tumors, synchronous or metachronous, that may involve the head and neck region as well as 
other organs, predominantly the lungs5 
1.2 
Chemotherapy for Locoregionally Advanced Disease 
The addition of chemotherapy with RT to the overall treatment plan in patients with locoregionally 
advanced head and neck cancer has been studied in an effort to improve organ prese1vation, locoregional, 
and distant control, and srnvival rates over RT alone. Reseai·ch studies have evaluated the use of induction 
(neoadjuvant) or adjuvant chemotherapy, as well as conc01nitant chemotherapy and radiation. The 
primaiy goal of such research is to improve local control and srnv ival. 
1.3 
Combined Modality Therapy for Organ Preservation 
An imp01tant goal of adding chemotherapy to radiation therapy is to improve local control and avoid 
mutilating surge1y , therefore, achieve organ prese1vation in patients  with resectable disease. Two-phase 
III randomized tiials, one by the VA La1yngeal Study Group and the other by EORTC, showed that organ 
prese1v ation is feasible in la1yngeal and hypophaiyngeal cancers. In both studies, induction chemotherapy 
with cisplatin and 5-FU followed by radiation therapy in responders allowed for organ prese1vation 
without a comprolnise in srnvival compai·ed to standard management with surgical resection followed by 
postoperative radiation6.7. However, one-third or more of patients required laiyngectomy for treatment 
failure. In the VA laiyngeal cancer study, the laiynx was prese1ved in 64% of all patients assigned to the 
induction chemotherapyaim, whereas in the EORTC ti"ial, in wh ic h a complete response was mandato1y 
to proceed with organ prese1vation, the 5-yeai· srnvival with a functioning la1ynx (censo li ng data for local 
failures only) was 35%, if all patients (n=l OO) who received induction chemotherapy were considered, 
and 58%, if only the group of 52 patients who achieved a complete response to induction chemotherapy 
and received radiation therapy were considered in analysis6. 


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A multicenter phase III randomized study evaluated the role of concomitant chemoradiation in lruyn gea l 
cancer (RTOG 91-11)8. T his th ree -aim study compru·ed the organ preservat ion strategy used in the VA 
lruyn gea l study to radiotherapy alone (without induction chemotherapy), and to concomitant 
chemoradiotherapy with single-agent cisplatin. Although no differences in survival were observed 
between aims, laiyngeal preservation was optimal in the concomitant chemoradiation treatmentaim. 
Therefore, concwTent che morad iation is now considered the standru·d regimen for organ prese1vation in 
the management of la1yngeal cancer. 
1.4 
Concomitant Chemoracliotherap y 
T he th eoretica l rat iona le and clinical experience of using concomitant chemoradiotherapy in patients with 
solid tumors has been reviewed9 10. For head and neck cancer this concept is prutic ul ar ly attract ive. It is 
hoped that chemotherapy will be successful at treating micrometastatic systemic disease while also 
enhancing the locoregionalefficacy of radiotherapy. Most of the older trials have used infusional 5-FU as 
the radiosensitizer based on work initially published by Byfield et al11 . The add ition of cisplati n12•13 , or 
cisplatin with 5 -FU / leucovorin and hyperfractionated radiotherapy14, or hydroxyurea15 16 in phase I or II 
studies have led to ve1y encouraging response and smv:ival data. In a randomized study, Merlano et al17 
demonstrated signific antly increased swvival in patients with unresectable disease treated with 
radiotherapy alternating with cisplatin and bolus 5-FU compared to patients treated with radiotherapy 
alone. 
A meta-analysis that included 63 randomized studies conducted between 1965 and 1993, demonstrated an 
absolute swv ival benefit of 8% at 5 yeru·s with conc 01nitant chemotherapy and radiotherapy versus 
radiation therapy alone18 . More recently, multiple randomized phase III trials have conclusively 
demonstrated that concwTent chemorad iotherapy is supe rior to radiation therapy alone in locally 
advanced head and neck cancer8•1·9 23.The above tiials predominantly enrolled patients with unresectable 
head and neck cancer, whereas three of these tii als were site-specific8 20 22 
Three randotnized t1ials used combined chemotherapy with platinum and 5-FU along with conventional 
or hyperfractionated radiotherapy. 19 21and three others used cisplatin with conventional radiation8 22 23 
Most of these studies favored concomitant chemoradiotherapy with an approximately 20% gain in 
swvival at three to five years (approximately 30% versus 50%), whereas the study by Forastiere et al24 
showed that concomitant chemoradiotherapy with cisplatin in resectable la1yngeal cancer is supe1ior in 
tenns of la1yngeal prese1vation8 
1.5 
Radiation plus Cisplatin for Locally Advanced Head and Neck Cancer 
A number of randomized  ttials in U.S.  have established conventional  radiotherapy plus cisplatin 100 
mg/m2 eve1y 3 weeks as the standai·d non-surgical treatment ofl ocally advanced head and neck cancer. In 
unresectable disease and nasopha1yngeal cancer a smv ival advantage was demonsti·atedover radiotherapy 
alone22 23 , whereas in la1yngeal cancer, concmTent chemoradiotherapy with cisplatin resulted in a higher 
rate of organ prese1vation8 
For unresectable head and neck squamous cell carcinoma, concmTent chemoradiotherapy has emerged as 
standru·dtherapy after the results of a randomized phase III tt·ial conducted by the Southwest Oncology 
Group (SWOG) and Eastern Cooperative Oncology Group (ECOG)23. This trial enrolled 295 patients 
.


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with umesectable squamous cell head and neck cancer, before closing to slow accrual. So far, it is the 
only study that has allowed a comparison, even indirectly, between single and combination 
chemotherapy. Three treatment anns were compared: (A) conventional radiotherapyalone (70 Gy at 2 Gy 
per day); (B) conventional radiotherapy plus single-agent cisplatin 100 mg/m2 eveiy 3 weeks; and (C) 
split course radiotherapy with concutTent cisp latin 75 mg/m2 on day 1 and 5-FU 1000 mg/m2/d as a 
continuous infusion, on days 1-4, repeated eveiy 4 weeks. Preliminaiy results showed an improvement of 
3-yeai· overall survival with single-agent cisplatin compai·ed to radiotherapy alone, from 20% to 37% 
(p=0.016). Survival rates between the two chemotherapy arms and between CRT and radiotherapy alone 
were not significantly different. Split course radiotherapy has been implicated for the suboptimal 
perfoimance of the cisplatin and 5-FU aim in this study. 
In laiyngeal cancer, RTOG 91-11 showed that the optimal laiyngeal preservation strategy is concutTent 
chemoradiotherapy8 This three-aim study, the goal of which was to deteimine whether the addition of 
chemotherapy to radiotherapy is necessaiy to achieve laiyngeal preservation, compared the laiyngeal 
preservation strategy used in the VA laiyngeal study consisting of induction chemotherapywith cycles of 
cisplatin and 5-FU, followed by radiotherapy for responders  (aim A) to concutTent chemoradiotherapy 
with cisplatin 100 mg/m2 administered eveiy three weeks (aim B),  and radiotherapy  alone  (aim  C).  A 
total of 510 patients were analyzable, and the median follow-up at the time of preliminaiy analysis was 30 
months. Sixty-five percent of patien ts received all three cycles of single-agent cisplatin during concutrnnt 
chemoradiotherapy. Grade 3 or 4 mucositis was seen in 33% of patients in aim  A,  53% in rum B, and 
36% in rum C. An advantage in overall survival could not be demonstrated with the use of chemotherapy, 
in spite of a decrease in the rate of dist.ant metas tasis; howeve r, lruyn gec tomy -free sutvival and lruyn gea l 
preseiv at ion rates were higher in the concutTent chemora diotherapy aim. At 2 yeru·s, lruyn gectomy-free 
sutvival rates were 58%, 68% (p=0.07 versus A), and 53%, and la1yngeal preseivation rates 74%, 88% 
(p=0.0047 versus A), and 69% for aims A, B, and C, respectively. 
ConcutTent chemoradiother apy with cisplatin has become standa rd therapy of locally advanced 
nasopha1yngeal carcinoma25. Updated results of the Intergroup ttial in nasophruyn gea l cru·cino ma 
demonstt·ated a 5-ye ar sutv ival of 67% versus 37% (p<0.001) and a 5-year PFS of 59% versus 29% 
(p<0.001) for patients tt·eated with chemoradiotherapy versus radiotherapy alone26  Toxicities with 
concutTen t therapy were increased but tolerable. Treatment deliveiy of adjuvant chemotherapy was 
suboptimal; 33% of patients received no adjuvant chemotherapy. Also, only two-thirds of patientscould 
receive all three doses of concun ent cisplatin, a finding consistent among randomized studies with this 
regimen (e.g. laiyngeal R91-l l and R95-01). 
While radiation plus high-dose cisplatin (i.e. 100 mg/m2 eveiy 3 weeks x 3 during radiation) has become 
a st.andat·d regimen for the tt·eatment ofl ocally advanced SCCHN,8 24   5,  this regimen results in 
considerable toxicities, including grade 3-4 mucositis in about 50% of patients as well as in several out- 
of-field toxicities, including nausea/vomiting,nephrotoxicity and others. As noted, about one-third of 
patients cannot receive the third cisplatin dose due to the onset of toxicities. This obseivation had led 
many groups to either reduce the dose of cisplatin to 75 mg/m2 eveiy 3 weeks (for example, ongoing 
ECOG study E3303), or to use lower dosages on a weekly schedule of administration when cisplatin is 
combined with other agents and RT. In chemoradiotherapy regimens, weekly cisplatin doses of 20-40 


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mg/m2 have been previously investigated and well tolerated. Low dose weekly cisplatin (20 mg/m2 alone 
combined with radiation did not result in a smvival benefit in a phase III trial that compared radiation plus 
cisplatin with radiation alone28. A weekly cisplatin dose of20 mg/m2 used incombination with paclitaxel 
and RT was shown to be feasible and active in an RTOG study29 . Weekly cisplatin 40 mg/m2 with RT, 
showed improved smvi val over radiation alone in patients with locally advanced nasopharyngeal cancer30 
A weekly cisplatin dose of 30 mg/m2 was employed in combination with cetuximab and RT in a recently 
completed phase II randomized trial by RTOG (0234)31 . 
The optimal chemotherapy regimen for incorporation into combined modality therapy has yet to be 
determined. It is unclear whether combination chemotherapy regimens are superior to single-agent 
chemotherapy in this setting. 
1.6 
Induction Chemotherapy 
Induction chemotherapy has the goal of "downstaging" the tumor but more importantly to eradicate early 
micrometastatic disease and therefore improve distant-site control. The rationale for using this 
investigational approach has been reviewed4 27 28  Most regimens are used for 2 to 3 cycles, including the 
widely used combination of cisplatin and continuous infusion 5-FU29  34    The response rates for untreated 
patients with locally advanced head and neck cancer range between 60-90%, with complete response rates 
of 20-50%35. Pathologic complete responses are documented in two-thirds of patients with a clinical 
complete response, and this is associated with a favorable prognosis35. The toxicity from induction 
chemotherapy is considerable though and severe and, occasionally, fatal toxicity may occm with the 
cisplatin and 5-FU regimen, or other regimens. 
In the past decade, multiple randomized studies have compared induction chemotherapy followed by 
definitive locoregional treatment versus immediate locoregional treatment35. Onl y one s tudy , conducted 
by French investigators, which included patients with oropha1yngeal cancer, demonstrated a smvival 
benefit with neoadjuvant chemotherapy versus locoregional therapy alone36. In addition, subset analysis 
of two other randomized studies showed a smvival advantage with induction chemotherapy37 38 
Paccagnella et al showed an advantage in the subset of patients with unresectable disease who received 
radiation as their locoregional therapy37 , whereas Richard et al, who employed intraarterial chemotherapy, 
found a smvival difference in the subgroupof patients with floor of mouth cancers38. However, several 
trials suggested that chemotherapy in the neoadjuvant or adjuvant setting results in a reduced incidence of 
distant metastases as site of first failme6 7 37.39 2 _ In order to improve the efficacy of induction therapy, 
newer combination regimens (e.g. taxane-based) are cmTently being evaluated in this setting. 
1.7 
Cisplatin and Docetaxel 
Cisplatin and docetaxe l have been combined in phase II ttials in recmrent or metastatic head and neck 
cancer. The regimen is active with response rate between 33-54%43-45 This is at least comparable to the 
activity of cisplatin/5-FU and cisplatin/paclitaxel in the recmTent/meta static disease setting. Cisplatin and 
docetaxel is well tolerated even in the palliative care setting.The FDA has approved cisplatin and 
docetaxel for first-line therapy of metastatic NSCLC. The commonly used doses are 75 mg/m2 for each 
dtug on day 1. A phase II tt·ial of cisp latin and docetaxel conducted by the EORTC rep01ted an object ive 
response rate of 89% in 22 previously untreated patients with locally advanced or recmTenthead and neck 
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cancer44. Another study repo1ted a response rate of 55% in patients with stage IV, locally advanced, head 
and neck cancer46. Several randomized studies have shown that triple combination with cisplatin/5- 
FU/docetaxel (TPF) improves overall survival (OS) and progression- free survival (PFS) in compaiison 
with the combination of cisplatin/5-FU (PF)73 74 
A recently published randomized phase II study investigated the addition of induction cisplatin and 
docetaxel to chemoradiotherapy for locally advanced nasophatyngeal cancer. Among 65 eligible patients 
with advanced nasopha1yngeal cai·cinoma, 34 patients received neoadjuvant docetaxel 75 mg/m2 and 
cisplatin 75 mg/m2 eve1y 3 weeks for 2 cycles followed by cisplatin 40 mg/m2/ weekly concmrnnt with 
radiation, whereas 31 patients were randomized to receive the same chemoradiotherapy without induction 
therapy. Patients who received induction therapy had superior PFS and OS 78. 
1.8 
Epidermal Growth Factor Receptor (EGFR) and Cetuximab 
 
1.8.1 
EGFR 
The epidennal growth factor receptor (EGFR) is a member of the erb B receptor tyrosine kinase family 
that also includes erbB,-2 erbB-3, and erbB-428. It consists of an extracellulai·ligand-binding domain, a 
transmembrane region that anchors the receptor to the plasma membrane, and a cytoplasmic region 
containing a tyrosine kinase domain. Among the known natural ligands of EGFR include epidennal 
growth factor (EGF) and transfonning growth factor a, (TGF-a) which both activate the receptor by 
binding to the extracellular domain and inducing the fom1ation of receptor homodimers or heterodimers, 
followed by internalization of the receptor/ligand complex and auto-phospho1ylation. It is now accepted 
that the EGFR signal transduction network plays an imp01tant role in multiple tum01igenic processes , 
includ ing cell cycle progression, angiogenesis, and metastasis, as well as protection from apoptosis28•29. In 
this signal network, erbB-2 is the major paitner of EGFR because activated heterodimer complexes 
containing erbB-2 are more stable at the cell smface than complexes containing other EGFR family 
members30 31 In addition erb B-2 can decrease the rate of ligand dissociation from the cognate receptor 
• . 
EGFR32. 
 
1.8.2 
EGFR Inhibition and the Cell Cycle 
The effects of EGFR blockade on  cell cycle progression have been investigated in several hmnan cell 
types, including DiFi colon adenocarcinoma cells, non-transf01med breast epithelial MCFIOA cells , A43 1 
squamous epithelial cai·cinoma cells, and DU145 prostatic cancer cells. These studies suggest that 
blocking EGFR with monoclonal antibodies such as cetuximab leads to cell cycle atTest in G1 which is 
accompanied by a decrease in cyclin dependent kinase (CDK) 2 activity, and an increase in the expression 
of CDK inhibitor p27K1Pl33 34 In addition to inducing GI-phase atTes,t EGFR blockade was also shown 
to lead to cell death via apoptosis in DiFi colon adenocarcinoma cells35. 
1.8.3 
Cet11ximab 
Cehtximab binds specifically to the epide1mal growth factor receptor (EGFR, HERi , c-ErbB-1) on both 
nonnal and tumor cells, and competitively inhibits the binding of epide1mal growth factor (EGF) and 
other ligands, such as transf01ming growth factor- alpha36. Binding of cehlximab to the EGFR blocks 
phosph01ylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, 


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induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor 
production. The EGFR is constitutively expressed in many n01mal epithe lial tissues , incl uding the skin 
and hair follicle. Overexpression of EGFR is also detected in many human cancers including those of the 
colon and rectum37 
In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of 
tumor cells that over-express the EGFR. No anti-ttllllor effects of cettIXimab we re observed in h1llllan 
tumor xenografts lacking EGFR expression. The addition of cettIXimab to i1inotecan or iti notecan plus 5- 
fluorouracil in animal studies resulted in an increase in anti-tumor effects compared to chemotherapy 
alone. 
1.8.4 
Human Pharmacokinetics 
Cetuximab administered as monotherapy or in combination with concomitant chemotherapy or 
radiotherapy exhibits nonlinear phaim acokinetics36 The ai·ea under the concentration time curve (AUC) 
increased in a greater than dose proportional manner as the dose increasedfrom 20 to 400 mg/m2. 
Cetuximab cleai·ance (Cl) decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 
mg/m2, and at doses >200 mg/m2, it appeai·ed to plateau. The volume of disttibution (Vd) for cetuximab 
appeai·ed to be independent of dose and approximated the vascular space of 2-3 L/m2 
Following a 2-hour infusion of 400 mg/m2 of cetuximab, the maximum mean semm concentration 
(Cmax) was 184 µg/mL (range: 92-327 µg/mL) and the mean elitnination half-life was 97 hours (range 
41-213 hours). A I-hour infusion of 250 mg/m2 produced a mean Cmax of 140 µg/mL (range 120-170 
µg/mL). Following the recommendeddose regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), 
cetuximab concentrations reached steady-state levels by the third weekly infusion with mean peak and 
trough concentt·aitons across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. The mean 
half-life was 114 hours (range 75-188 hours). 
Cen1ximab administe red as monotherapy or in combination with concomitant chemotherapy or 
radiotherapy exhibits nonlinear phaim acokinetics.The phaimacokinetics of cen1ximab were similai·in 
patients with squamous cell carcinoma of the head and neck (SCCHN) and those with colorectal cancer36 
 
 
1.8.5 
Randomized Clinical Trials of Cetuximab in Head and Neck Cancer 
 
1.8.5.1 
Cetuximab in Locally Advanced Squamous Cell Carcinoma of Head and Neck 
The efficacy and safety of cetuximab were studied in combination with radiation therapy in a randomized, 
controlled ttial of 424 patients with locally or regionally advanced squamous cell cai·cinomaof the head 
and neck versus radiation alone38. In a multicenter contt·olled clinical ttial, 424 patients with stage III/IV 
SCC of the orophaiynx, hypopha1ynx, or laiynx with no p1ior thera py were randomized 1:1 to receive 
cetuximab plus radiation therapy (211 patients) or radiation therapy alone (213 patients). Stratification 
factors were Kamofsky Performance Status (60-80 versus 90-100), nodal stage (NO vers us N+), tumor 
stage (Tl -3 versus T4 using American Joint Committee on Cancer 1998 staging c1i te1ia), and radiation 
therapy fractionation (concomitant boost versus once-daily versus twice daily). Radiation therapy was 
administered fonn 6-7 weeks as once daily, twice daily or concomitant boost. The planned radiation 
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therapy regimen was chosen by the investigator prior to enrollment. For patients with Nl neck disease, a 
post-radiation  therapy next dissection  was recommended. Staiting 1 week before radiation, cetuximab 
was administered as a 400-mg/m2 initial dose, followed by 250 mg/m 2 weekly for the duration of 
radiation therapy (6-7 weeks). All cetuximab-treated patients received a 20-mg test dose on Day 1. 
Cetuximab was administered 1 hour p1ior to radiation therapy, beginning week 2. Of the 424 randomized 
patients, 80% were male and 83% were Caucasian. The median age was 57 yeai·s (range 34-83). There 
were 258 patients enrolled in US sites (61%) and 166 patients (39%) in non-US sites. Ninety percent of 
patients had baseline Karnofsky Perf01mance Status 80%; 60% had orophaiyn geal, 25% laiyn geal, and 
15% hypophaiyn geal p1imaiy tumors; 28% had AJCC T4 tumor stage. The patient characte1istics were 
similar across the sn1dy aims. Fifty-six percent of the patients received  radiation therapy with 
concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen. 
The main outcome measure oft his tiial was duration ofl ocoregional control. Overall survival was also 
assessed. Results are presented below: 
Table 1 Clinical Efficacy in Locoregionally Advanced SCCHN 
 
Cetuximab + 
Radiation 
(n = 211) 
Radiation 
Alone 
(n = 213) 
Hazard Ratio 
(95% CI*) 
Stratified 
Log-rank 
p-value 
Locoregional control 
MedianDuration 
24.4 mo 
14.0mo 
0.68 (0.52-0.89) 
0.005 
Overall Survival 
Medianduration 
49.0 mo 
29.3 mo 
0.74 (0.57-0.97) 
0.03 
*Cl = confidence inteival. 
 
1.8.5.2 
Cetuximab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck 
More recently the results of EXTREME t:rial47 have been repo1et d. In this multicenter study 442 patients, 
with unti·eated recunent or metastatic squamous cell carcinoma of the head and neck, enrolled. 220 
patients were randomly assigned to receive cisplatin (at a dose of 100mg/m2, on day 1) plus 5FU (at  a 
dose of 1000mg/m2, for 4 days) eve1y three weeks for a maximum of 6 cycles and 222 patients to receive 
the same regimen plus cetuximab (at an initial loading dose of 400mg/m2,  then weekly doses of 
250mg/m2) for 6 cycles. Patients who didn't progress continued monotherapy of cetuximab until disease 
progression. The patients in each coho1twere well- balanced regarding gender, age, pe1formance status 
(PS, )  primaiy tumor site, extent of disease and histologic type. About ninety percent of the patients had 
PS> 80%. Results are presented below: 


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Table 2 Clinical Efficacy in Locoregionally Advanced SCCHN 
 
Cetuximab 
+ chemo 
Chemo Alone 
Hazard Raffo or 
Odds Ratio 
(95% CI*) 
p-value 
Overall survival 
10.1 mo 
7.4mo 
0.80 (0.64-0.99) 
0.04 
Progrt>ss i o n Free 
Survival 
5.6mo 
3.3 mo 
0.54 (0.43-0.67) 
<0.001 
Time to treatment 
failure 
4.8mo 
3.0mo 
0.59(0.48- 0.73) 
<0.001 
Disease control 
81% (75-86%) 
60% (53-67%) 
Odds Ratio 
2.88 (1.87-4.44) 
<0.001 
*Cl = confidence interval. 
A phase ill tlial ofradiation cisplatin with or without cetuximab is ongoing in the RTOG (0522). 
 
1.8.6 
Other Cetuximab Trials in Head and Neck Cancer 
Cetuximab alone was studied in a single-rum, multicenter clinical trial in 103 patients with recurrent or 
metastatic SCCHN with documented progression within 30 days after 2-6 cycles of a platinum-based 
chemotherapy48.  Patien ts received a 20-mg test dose of cetuximab on Day 1, followed by a 400-mg/m2 
initial dose, and 250 mg/m2 weekly until disease progression or unacceptable toxicity. Upon progression, 
patients were given the option ofr eceivingcetuximab plus the platinum regimen that they failed p1i or to 
emollment. Tumor response and progression were assessed by an Independent Radiographic Review 
Committee (IRC). The median age was 57 years (range 23-77), 82% were male, 100% Caucasian, and 
62% had a Kamofsky perfmmance status of 80. The objective response rate on the monotherapy phase 
was 13% (95% confidence interval 7%-21%). Median duration of response was 5.8 months (range 1.2-5.8 
months). 
A phase II study conducted at Memorial-Sloan Kettering Cancer Center explored the combination of 
radiation, cisplatin, and cetuximab49. This study employed altered fractionation radiotherapy with 
accelerated boost. There were 2 deaths during treatment (one patient died of pneumonia and the other 
from unknown cause) in a total of 22 patients and 3 other out-of field serious adverse events (arrhythmia, 
myocru·dial infarction , and bacteremia). However, the progression-free survival was promising (80% at 2 
yeru·s)49 .  It was thought that a lower dose of cisplatin than 100 mg/m2 would be safer with this 
combination regimen. A phase II study with cisplatin, radiation, and cetuximab was completed in ECOG 
(E3303). This study employed a lower cisplatin dose of75 mg/m2eve1y 3 weeks x 3. 
Expe1ience with TPE followed by XPE at the University of Pittsburgh 
The proposed study is building on our previous expe1i ence at the University of Pittsburgh with induction 
with cisplatin, docetaxel, and cetuximab (TPE). This phase II tlial (UPCI 05-003)completedaccrnal of 39 
patients in 2007. Results have been presented at ASCO 2008 (abst1·act 6002) and the manuscript was 
published in JCO in 2010 (Argiris et al JCO 2010). The treatlnent regimen consisted of 3 cycles of 
induction (TPE) therapy with docetaxel (T) 75mg/m2 dl , cisplatin (P) 75mg/m2 dl and cetuximab (E) 


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dl ,8,15 (q21d) followed by (XPE) RT (X) 70Gy, cisplatin (P) 30mg/m2 weekly and then cetuximab (E) 
maintenance for 6 months. Treatment was associated with expected and manageable toxicities.. Of 39 
emolled patients, 36 had stage IV disease and 23 an oropha1yngeal p1ima1y.Acute toxicities during TPE 
includedneutropenic fever (10%) and dmi ng XPE, grade 3 or 4 oral mucositis (54%) and 
hypomagneselnia (39%). After TPE, we observed two complete responses (CRs) and 30 partial responses 
(PRs), overall response rate (ORR) of 86% (95% CI, 75% to 98%) in 37 evaluable patients. The complete 
response using PET p01tion of PET/CT was 21%. After XPE, we observed an ORR of 100% (95% CI, 
91% to 100%), 24% CRs and 76% PRs, in 33 evaluable patients. In another paper by Passero et al 
(Annals of Oncology 2010;21:2278-83), we demonstrated that reposnse by PET but not using RECIST 
1.0 con elated with progression-free survival. With a median follow-up of 36 months, 3-year progression- 
free smvival and overall smvival were 70% and 74%, respectively. Eight patients progressed in 
locoregional sites, three in distant, and one in both. HPV positivity was not associated with treatment 
efficacy. No progression-free patient remained G-tube dependent. The H&N subscale QOL scores 
showed a significant decrement at 3 months after XPE, which normalized at I year. We concluded that 
this cetuximab-containing regimen resulted in excellent long-te1msmv ival and safety, and wa1rnnts 
fmther evaluation in both HPV-positive and -negative head and neck cancer. 
Safety of Cetuximab in Clinical Tti als 
1.8.6.1 
Anticipated Adverse Events 
Squamous Cell Cancer of the Head and Neck 
Except where indicated, the data desc1ibed below reflect exposure to cehlximab in 208 patients with 
locally or regionally advanced HNSCC who received cetuximab in combination with radiation and as 
monotherapy in I 03 patients with recmrnnt or metastatic HNSCC. Of the 103 patients receiving 
cetuximab monotherapy, 53 continued to a second phase with the combination of ceh1ximab plus 
chemotherapy. Patients receiving cetuximab plus radiation therapy received a median of 8 doses (range 1- 
11 infusions). The population had a median age of 56; 81% were male and 84% Caucasian. Patients 
receiving cetuximab monotherapy received a median of 11 doses (range 1-45 infosions). The population 
had a median age of 57; 82% were male and 100% Caucasian. 
The most se1·ious adverse reactions associated with cetuximab in combination with radiation therapy in 
patients with head and neck cancer were: 
• 
Infusion reaction (3%) 
• 
Cardiopulmona1y  atTest (2%) 
• 
De1matologic toxic ity (2.5%) 
• 
Mucositis (6%) 
• 
Radiation de1matitis (3%) 
• 
Confosion (2%) 
• 
Dian hea (2%) 
• 
Fomteen (7%) patients receiving cetuximab plus radiation therapy and 5 (5%) patients receiving 
cetuximab monotherapy, discontinued treatment primai·ily because of adverse events 
• 
The most common adverse events seen in 208 patients receiving cetuximab in combination with 
radiation therapy were acnefonn rash (87%), mucositis (86%), radiation de1matitis (86%), weight 
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loss (84%), xerostomia (72%), dysphagia (65%), asthenia (56%), nausea (49%), constipation 
(35%), and vomiting (29%) 
• 
The most common adverse events seen in 103 patients receiving cetuximab monotherapy were 
acnefonn rash (76%), asthenia (45%), pain (28%), fever (27%), and weight loss (27%). 
 
The data in the table that follows are based on the experience of 208 patients with locoregionally 
advanced HNSCC treated with cetuximab plus radiation therapy compared to 212 patients treated with 
radiation therapy alone. 
Table 3 Incidence of Selected Adverse Events ( 10%) in Patients with Locoregionally Advanced HNSCC 
Body System 
PrefenedTenn 
Cetuximab plus Radiation 
(n=208) 
RadiationTherapyAlone 
(n=212) 
Grades 
1 - 4 
Grades 
3 and4 
Grades 
1 - 4 
Grades 
3 and4 
% of Patients 
Body as a Whole 
Asthenia/Malaise 
56 
4 
48 
5 
Fever1 
29 
1 
13 
< l 
Headache 
19 
<1 
8 
<1 
Infusion Reaction2 
15 
3 
2 
0 
Infection 
13 
1 
9 
1 
Chills1 
16 
0 
5 
0 
Digestive 
Mucositis/Stomatitis 
93 
56 
94 
52 
Xerostomia 
72 
5 
71 
3 
Dysphagia 
65 
26 
63 
30 
Nausea 
49 
2 
37 
2 
Constipation 
35 
5 
30 
5 
Vmniting 
29 
2 
23 
4 
Anorexia 
27 
2 
23 
2 
Diauhea 
19 
2 
13 
1 
Dyspepsia 
14 
0 
9 
1 
Metabolic/Nutritional 
Weight Loss 
84 
11 
72 
7 
Dehydration 
25 
6 
19 
8 
Respiratory 
Pharyngitis 
26 
3 
19 
4 
Cough Increased 
20 
<1 
19 
0 
Skin/Appendages 
Acnefonn Rash3 
87 
17 
10 
1 
Radiation Dermatitis 
86 
23 
90 
18 
Application Site 
18 
0 
12 
1 
Reaction 
Pruritus 
16 
0 
4 
0 


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Table 3 Incidence of SelectedAdverse Events ( 10%) in Patients with Locore!rlona ll v Adva n ced HNSCC 
Body System 
Prefened Te1m 
Cetuximab plus Radiation 
(11=2 08) 
RadiationTherapy Alone 
( n = 212) 
Grades 
1 - 4 
I 
Grades 
3 and4 
Grades 
1 - 4 
I 
Grade s 
3 and4 
% of Patients 
1 Includes cases also reported as infilsion reactions. 
2 Infilsion reaction is defined as any event desc1ibed at any time dming the clinical study as "allergic reaction" or 
"anaphylactoidreaction" or any event on the first dayof dosing desc1ibed as "allergicreaction", "anaphylactoidreaction", 
"fever", "chills", "chills and fever" or "dyspnia". 
3 Acnefonn rash as defined as any event desc1ibed as "acne", " rash", " maculopapularash", "pustular rash", "d1yskin" or 
"exfoliative dermatitis". 
 
The data in the table below are based on the experience of 222 patients with recmrnnt or metastatic 
HNSCC treated with cetuximab plus chemotherapy compared to 220 patients treated with chemotherapy 
alone. 
 
Table 4 Incidence of Selected Adverse Events ( 5%) in Patients with Metastaticor recurrent 
HNSCC 
Event 
Cetuximab plus chemo 
(n=222) 
chemo Alone 
(n=220) 
Grades 
3 - 4 
Grade 4 
Grades 
3 - 4 
Grade4 
% of Patients 
Any event 
82 
31 
76 
31 
Neutropenia 
22 
4 
23 
8 
Anemia 
13 
1 
19 
I 
Thrombocytopenia 
11 
0 
11 
I 
Skin reaction* 
9 
2 
<l 
0 
Hypokalemia 
7 
1 
5 
<l 
Card iac events 
7 
5 
4 
3 
Vomiting 
5 
0 
3 
0 
Asthenia 
5 
< l 
6 
<l 
Anorexia 
5 
1 
1 
<l 
Hypomagne 
se m i a 
5 
4 
1 
<l 
*S kin reactions include: acne, msh, maculopapular rash, ceUulities, face edema, dry skin, erysipelas, folliculitsi, naildisorder, 
paronychia, skin hyperpigmentation and skin necrosis. 
 
 
Six patien ts (3%) developed infusion- related reaction grade 3 or 4. Grade 2 skin reaction was observed in 
about 35% of the patients in cetuximab group. 
Late Radiation Toxicity 
The overall incidence of late radiation toxicities (any grade) was higher in cetuximab in combination with 
radiation therapy compared with radiation therapy alone. The following sites were affected: saliva1y 


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glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous 
membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%), brain (11% versus 
9%), lung (11% versus 8%), spinal cord (4% versus 3%), and bone (4% versus 5%). The incidence of 
Grade 3 or 4 late radiation toxicities were generally similar between the radiation therapy alone and the 
cetuximab plus radiation treatment groups. 
1.8.6.2 
Infusion Reactions 
In clinical trials, severe, potentially fatal infusion reactions were rep01ted. These event s include the rapid 
onset of aiiway obstruction (bronchospasm, st:ridor and hoarseness), mticaria, and/or hypotension. In 
studies in advanced colorectal cancer, severe infusion reactions were obse1ved in 3% of patients receiving 
cetuximab plus iii.notecan and 2% of patients receiving cetuxiinab monotherapy. Grade 1 and 2 infusion 
reactions, including chills, fever, and dyspnea usually occmTing on the first day of initial dosing, were 
obse1ved in 16% of patients receiving cetuxiinab plus iti.notecan and 19% of patients receiving cetuximab 
monotherapy. 
A 20-mg test dose was administered intr·avenously over IO mi n u te s p1i.or to the initial dose to all patients 
in earlier studies. The test dose did not reliably identify patients at risk for severe allergic reactions. 
Severe infusion reactions occmTed with the administration of cetuxiinab in approximately 3% of patients, 
rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were associated 
with the first infusion of cetuximab despite the use of prophylacticantihistamines. These reactions were 
characte1i.zed by the rapid onset of aiiway obstrnction (bronchospasm, stridor and hoarseness), urticai.a, 
and/or hypotension. 
1.8.6.3 
Pulmonary Toxicity 
Interstitial lung disease (ILD) was rep01ted in 3 of 774 (<0.5%) patients with advanced colorectal cancer 
receiving cetuximab. Interstitial pnemnonitis with non-cardiogenicpulmona1yedema resulting in death 
was rep01ted in one case. Two patient s had pre-existing fibrotic lung disease and expe1i.encedan acute 
exacerbation of theiI·disease while receiving cetuximab in combination with iti.notecan. In the clinical 
investigational prograin, an additional case of interstitial pneumonitis was rep01ted in a patient with head 
and neck cancer treated with cetuximab and cisplatin. The onset of symptomsoccmrnd between the fomth 
and eleventh doses of treatment in all reported cases. 
1.8.6.4 
Dermatologic Toxicity 
In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the 
weekly human exposme (based on total body smfa ce ai·ea) resulted in dermatologic findings, including 
inflammation  at the injection site and desquamation of the  external integument50.  At  the highest dose 
level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similai·ly affected, and 
degenerative changes in the renal tubulai· epithelium occmTed. Death s due to sepsis were obse1ved in 50% 
(5/10) of the animals at the highest dose level beginning after approxiinately 13 weeks of treatment. 
In clinical studies of cetuxiinab, dennatologic toxicities, including acneform rash, skin dty ing and 
fissming, and inflammat01y and infectious sequelae (eg, blepharitis, cheilitis, cellulitis, cyst) were 
repo1t ed50. In patients with advanced colorectal cancer, acnefo1m rash was repo1t ed in 88% (686/774) of 


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all treated patients, and was severe (Grade 3 or 4) in 12% (79/633) of these patients. Subsequent to the 
development of severe de1matologic toxicities , complicat ions including S. aureus sepsis and abscesses 
requiiing incision and drainage were repo1ted. 
Non-suppura tive acnefo1m rash described as "acne", "rash", "maculopapular rash", "pustularrash", "diy 
skin", or "exfoliativede1matitis" was observed in patients receiving cetuximab plus ilinotecan or 
cetuximab monotherapy50. One or more of the de1matological adverse events were repo1t ed in 88% (14% 
Grade 3) of patients receiving cetuxilnab plus ilinotecan and in 90% (8% Grade 3) of patients receiving 
cetuxilnab monotherapy. Acnefmm rash most commonly occurred on the face, upper chest, and back, but 
could extend to the extremities and was characte1ized by multiple follicular- or pustular-appea1ing 
lesions. Skin diying and fissming were common in some instances, and were associated with 
inflammato1yand infectioussequelae (eg, blepha1itis, cellulitis, cyst). Two cases of S. aureus sepsis were 
repo1ted. The onset of acnefo1m ras h was general ly within the first two weeks of therapy. Although in a 
majmity of the patients the event resolved following cessation of treatment, in nearly half of the cases, the 
event continued beyond 28 days. 
A related nail disorder, occm1ing in 14% of patients (0.4% Grade 3), was characte1ized as a paronychial 
inflammation with associated swelling of the lateral nail folds of the toes and fingers, with the great toes 
and thumbs as the most commonly affected digits. 
1.9 
Induction Chemotherapy Followed by Chemoradiotherapy 
Squamous cell carcinomas of the head and neck are chemosensitive neoplasms. However, multiple 
randomized trials have failed to demonstrate that the addition of induction chemotherapy to surge1y 
and/or radiotherapy confers a survival advantage in patients with locally advanced head and neck cancer. 
The rationale of induction therapy was questioned and its use was thought to be expe1imental33 51 53 
ConcmTent chemoradiotherap y was felt to be the most promising approach and was studied extensively in 
the 1990s. Neve1theless, a number of studies of induction chemotherapy have shown a decreased rate of 
distant metastasis with the use of induction chemotherapy and a few have repo1t ed encouraging survival 
data. A study by Pacagnella et al that compared induction chemotherapy with cisplatin/5-FU followed by 
surge1y and/or radiation showed a survival benefit but only in patients with unresectable tumors37 
Domenge et al36 repmted the only positive trial that enrolled 318 patients with locally advanced 
oropha1yn geal cancer. Disease-free smvival was ilnproved in the induction chemotherapy arm but the 
difference did not reach statistical significance (p=O.1 1); overa ll smv ival was superior in the induction 
chemotherapy aim (p<0.05). These  two  tlials were included in a metaanalysis by Pignonet  al published 
in 200018. In this metaanalysis, when all induction chemotherapy studies were examined together, there 
was no smv ival benefit with induction chemotherapy. However, when the subset of ti·ials with 
platinum/5-FU was examined, a statistical significant ilnprovement in smvival with the addition of 
induction chemotherapy was obse1ved with a hazard ratio of0.88 (95% CI 0.79-0.97). A study by Taylor 
et al suggested that concmTent therapy on an alternate week schedule produced better disease control and 
comparable smvival to induction chemotherapy54. However, no study has evaluated the role of the 
addition of induction chemotherapy when concmrnnt chemoradiotherapy is used in both aims in head and 
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Multiple chemotherapy regimens have been tested in the induction setting in head and neck cancer. The 
most widely used has been cisplatin and 5-FU. Carboplatin may be inferior to cisplatin  as demonstrated in 
a randomized comparison between cisplatin/5-FU and carboplatin/5-FU in the induction setting55 Also, 
the activity of carboplatin/5-FU in recun ent/metastaticdisease is inferior to that of cisplatin/5-FU56 The 
combination of platinum and the taxanes has been paiticularly active in head and neck cancer. Moreover, 
the incidence of stomatitis seen with this regimen is less than what is observed when 5-FU is a pait of the 
regimen. Cai-bop latin and pacl i taxe l have been used in many studies with objective response rates 80% or 
higher57 . 
The combination of cisplatin and docetaxel is active in recmTent/metastatic head and neck cancer with 
objective response rates between 33-54%434 5 as well as in locally advanced head and neck cancer with 
objective response rates between 55-89%4446 which is compai·able to the activity of cisplatin/5-FU and 
cisplatin/paclitaxel. The feasibility of platinum-based induction chemotherapy for 2-3 cycles followed by 
cisplatin or paclitaxel concmTently with radiotherapy has been demonstrnted in multiple trials57 59 
However, no study has yet shown the feasibility of cisplatin/docetaxel followed by cisplatin concmrent 
with standard radiation. One of the concerns is whether cumulative toxicities from the induction regimen 
will compromise dose delive1ydming subsequentchemoradiotherapy. A consistent finding among sn1dies 
with cisplatin 100 mg/m2 eve1y 3 weeks plus radiation has been that all three doses of "high-dose" 
cisplatin can only be delivered in approximately 60% of patients. In this study, we will allow the use of 
cai·boplatin; if out of field cisplatin-related toxicities occm. 
Studies with cisplatin and 5-FU have shown that the response rate is higher with 3 versus 2 cycles60 
whereas a plateau may be reached after 3 cycles61. Shin et al have observed that with additional cycles of 
induction chemotherapy, the rate of complete response to carboplatin/ifosfamide/paclitaxel  increased 
from 23% after 2 cycles to 60% after 4 cycles62. For this study we elected to use 3 cycles of 
chemotherapy that will allow adequate systemic exposure to chemotherapy. An ongoing study in om 
institution is evaluating cisplatin and docetaxel followed by radiation and cisplatin 100 mg/m2 eve1y 3 
weeks x 3 in unresectable patients with head and neck cancer. 
1.10 BevacizumabClinical Experience 
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more than 5000 
patients and in multiple tumor types. In addition, data are available from 3,863 patients enrolled in two 
postmai·keting studies in metastatic colorectal cancer (CRC). Approximately 130,000 patients have been 
exposed to bevacizumab as a mai·keted product or in clinica l tria ls. Th e following discussion summarizes 
bevacizumab's safety profile and presents some of the efficacy results pe1tinent to this pa1ticulai·trial. 
Please refer to the bevacizumab Investigator Brochme for descriptions of all completed Phase I, II, and III 
tiials rep01ted to date. 
In a large phase III study (AVF2107g)63 in patients with metastatic colorectal cancer, the addition of 
bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF), to 
iii notecan/5-fluoromacil/leucovorin (IFL) chemotherapy resulted in a clinically and statistically 
significant increase in dmation of survival,  with a hazai·d ratio of death of 0.67 (median smv ival 15.6 vs. 
20.3 months; p < 0.001). Similar increases were seen in progression-free smvival (6.2 vs. 10.6 months; 
p < 0.001), overall response rate (35% vs. 45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; 


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p < 0.01) for the combination arm versus the chemotherapy only arm (bevacizumab Investigator 
Brochure, October 2005). 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was designated for 
pri01ity review and was approved on 26 February 2004 in the United States for first-line treatment in 
combination with IV 5-FU- based chemotherapy for subjects with metastatic colorectal cancer. 
Additional data from Phase III tlials in metastatic CRC (£3200)64, non- small cell lung cancer (NSCLC; 
£4599)65, and metastatic breast cancer (£ 2100)66 havealso demonsti·ated clinical benefit from 
bevacizumab when added to chemotherapy. In Study E3200, the addition of bevacizumabto FOLFOX 
chemotherapy resulted in improved overall survival compared with FOLFOX alone (13.0 vs. 
10.8 months, respectively, HR = 0.75; p < 0.01) in a populationof previously ti·eated CRC patients . 
There was also improved overall survival in first-line NSCLC patients (E4599) ti·eated with 
carboplatin/paclitaxel + bevacizumab compared with chemotherapy alone (12.3 vs. 10.3 months, 
respectively; HR = 0.80; p = 0.003). The results from this tiial were the basis for FDA approval of 
bevacizumab for use in combination with carboplatin + paclitaxel as first-line treatment of patients with 
unresectable, locally advanced, recurrent or metastatic, non-squamous NSCLC in October 2006. Finally, 
patients with unti·eated metastatic breast cancer (E2100) who received bevacizumab in combination with 
weekly paclitaxel had a marked improvement in PFS compared with chemotherapy alone (13.3 vs. 
6.7 months, respectively; HR = 0.48; p < 0.0001) (see the Bevacizumab Investigator Brochure for 
additional details). 
Safety Profile 
In the initial Phase I and II clinical tiials, four potential bevacizumab-associated safety signals were 
identified: hypertension, proteimnia, thromboembolic events, and hemon hage. Additional completed 
Phase II and Phase III studies of bevacizumab as well as spontaneous repo1t s have finther defined the 
safety profile of this agent. Bevacizumab-associated adverse events identified in phase III trials include 
congestive heait failure (CHF) p1imai·ily in metastatic breast cancer, gastrointestinal perforations, wound 
healing complications, and a1te1i al thromboembolic events (ATE). These and other safety signals ai·e 
described in finther detail as follows and in the bevacizmnab Investigator Brochure. 
Hypertension: An increased incidence of hype1et nsion has been observed in patients ti·eated with 
bevac izumab. Grade 4 and 5 hypertensive events ai·e rai·e. Cli nica l seque lae of hype 1t ens ion ai·e rare but 
have included hype1tensive crisis, hype1tensive encephalopathy , and reversib le posterior 
leukoencephalopathy syndrome (RPLS)67 68. 
There is no inf01m atio n on the effect of bevacizumab in patients with uncontrolled hype1tension at the 
time of initiating bevacizumab therapy. Therefore, caution should be exercised before initiating 
bevacizumab therapy in these patients. Monito1ing of blood pressure is recommended dming 
bevacizumab therapy. Optimal control of blood pressure according to standai·d public health guide lines is 
reco mmended for patients on ti·eatment with or without bevacizumab. 
Temporaiy intenu ption of bevacizmnab therapy is recommended in patients with hype1tension requiring 
medical therapy until adequate conti·ol is achieved. If hype1tension cannot be controlled with medical 


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therapy, bevacizumab therapy should be permanently discontinued. Bevacizumab should be permanently 
discontinued in patients who develop hypeitensive crisis or hypertensive encephalopathy. 
Prnteinuria : An increased incidence of proteinuria has been observed in patients treated with 
bevacizumab compared with control aim patients. In the bevacizumab-containing treatment aims of 
clinical tii als (across all indications), the incidence of proteinuria (repoited as an adverse event) was up to 
38% (metastatic CRC Study AVF2l 92g). The severity of proteimui a has ranged from asymptomatic and 
ti·ansient events detected on routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria 
events have been grade 1. NCI-CTC Grade 3 proteinuria was repmted in up to 3% of bevacizumab- 
ti·eated pa tients , and Grade 4 in up to 1.4% of bevacizumab-treated patients. The proteinuria seen in 
bevacizumab clinical trials was not associated with renal impailment and rai·ely requil·edpennanent 
discontinuation of bevacizumab therapy. Bevacizumab should be discontinued in patients who develop 
Grade 4 proteinuria (nephrotic syndrome) 
Patients with a histoiy of hypeitension may be at increased iisk for the development of proteinuria when 
ti·eated with bevacizumab. There is evidence from the dose-finding, Phase II tiials (AVF0780g, 
AVF0809s, and AVF0757g) suggesting that Grade 1 proteinuria may be related to bevacizumab dose. 
Proteinmi a will be monitored by mine protein: creatinine (UPC) ratio at least eveiy 6 weeks. If the UPC 
ratio is not available, a dipstick mi nalysis may be used to allow ti·eatment to proceed. 
Thromboembolic Events: Both venous and ait eiial thromboembolic(TE) events, ranging in seveii ty 
from catheter-associated phlebitis to fatal, have been repoited in patients treated with bevacizumab in the 
colorectal cancer tlials and, to a lesser extent, in patients ti·eated with bevacizumab in NSCLC and breast 
cancer tlials. 
Venous Thrnmboembolism (including deep venous thrombosis, pulmonary embolism, and 
thrombophlebitis): In the phase III pivotal tli al in metastatic CRC, there was a slightly higher rate of 
venous TE events in patients ti·eated with bevacizumab plus chemotherapy compai·edwith chemotherapy 
alone (19% vs. 16%). 
In Study AVF2107g, a Phase III, pivotal tlial in metastatic CRC, VTE events, including deep venous 
thrombosis, pulmonaiy embolism, and thrombophlebitis, occmrnd in 15.2% of patients receiving 
chemotherapy alone and 16.6% of patients receiving chemotherapy + bevacizumab. 
The incidence of NCI-CTC Grade 3 venous VTE events in one NSCLC tiial (E4599) was higher in the 
bevacizumab-containing aim compared to the chemotherapyconti·ol aim (5.6% vs. 3.2%). One event 
(0.2%) was fatal in the bevacizumab-containing aim; not fatal events were repoited in the 
cai·boplatin/paclitaxel aim (see Bevacizumab Investigator Brochure). In metastatic CRC clinical ti·ials, the 
incidence of VTE events was silnilai·in patients receiving chemotherapy+ bevacizumab and those 
receiving the control chemotherapy alone. 
In clinical tli als across all indications the overall incidence of VTE events was 2.8%- 17.3% in the 
bevacizumab-containing aims compared with 3.2%- 15.6% in the chemotherapycontrol aims. Theuse of 
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chemotherapy alone. However, patients with metastatic CRC who receive bevacizumab and experienced a 
VTE event may be at higher risk for rec1mence of VTE event. 
AI'tel'ial Thro mbo emboti c Events: An inc reased incidence of ATE events was observed in patients 
treated with bevacizumab compared with those receiving control treatments. ATE events include 
cerebrovascular accidents, myocardial infarction, transient ischemic attacks (TIAs), and other ATE 
events. In a pooled analysis of data from five randomized Phase II and III trials (mCRC [AVF2107g, 
AVF2192g, AVF0780g]; locally advanced or metastatic NSCLC [AVF0757g]; metastatic breast cancer 
[AVF2119g]), the incidence rate of ATE events was 3.8% (37 of963) in patients who received 
chemotherapy+ bevacizumab compared with 1.7% (13 of782) in patients treated with chemotherapy 
alone. ATE events led to a fatal outcome in 0.8% (8 of963) of patientstreated with 
chemotherapy+ bevacizumab and 0.5% (4 of782) of patientstreated with chemotherapy alone. 
Cerebrovascular accidents (including TIAs) occurred in 2.3% of patients treated with 
chemotherapy+ bevacizumab and 0.5% of patients treated with chemotherapy alone. Myocardial 
infarction occ1med in 1.4% of patients treated with chemotherapy+ bevacizumab compared with 0.7% of 
patients treated with chemotherapy alone (see the Bevacizumab Investigator Brochure for additional 
details). 
Aspirin is a standard therapy for primaiy and secondaiy prophylaxis of aite1i al thromboembolic events in 
patients at high risk of such events, and the use of aspitin ::: 325 mg daily was allowed in the five 
randomized studies discussed above. Use of aspit-in was assessed routinely as a baseline or concomitant 
medication in these tria,ls though safety analyses specifically regai·dingaspit-in use we re not prep lanned. 
Due to the relatively small numbersof aspit·in users and a1terial thromboembolic events, retrnspective 
analyses of the ability of aspi1in to affect the risk of such events were inconclusive. However, similarly 
retrospective analyses suggested that the use of up to 325 mg of aspitin daily does not increase the1isk of 
grade 1-2 or grade 3-4 bleeding events, and similar data with respect to metastatic colorectal cancer 
patients were presented at ASCO 2005 (Hambleton et al., 2005). Frnt her analyses of the effects of 
concomitant use of bevacizumab and aspirin in colorectal and other tumor types ai·e ongo in g. 
Ga stl'ointestinal Perforation Patients with metastatic carcinoma may be at increased 1i sk for the 
developmentof gastrointestinalperforation and fistula when treated with bevacizumab and chemotherapy. 
Bevacizumab should be pe1manently discontinued in patients who develop gastrointestinal perforation. A 
causal association of intra-abdominalinflammat01y processes and gastrointestinal perforation to 
bevacizumab treatment has not been established. Neve1thele,ss caution should be exercised when treating 
patients with intra-abdominal inflammat01y processes with bevacizumab. Gastrointestinal pe1foration has 
been rep01ted in other hi als in non-colorectal cancer populations (e.g., ova1ian, renal cell, pancreas, 
breast, and NSCLC) and may be higher in incidence in some tumor types. 
Fistula: Bevacizumab use has been associated with se1ious cases of fistulae including events resulting in 
death. Fistulae in the GI h·act ai·e common (1%- 10% incidence) in patients with metastatic CRC, but 
uncommon (0.1%- 1%) or rai·e  (0.01%-0 .1%) in other indications. In addition, fistulae that involve ai·eas 
of the body other than the GI h·act (e.g ., tracheoesophageal , bronchop leural, urogenital, biliaiy) have been 
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reports . Events were repo1ted at various timepoints during treatment, ranging from 1 week to 1 year 
following initiation of bevacizumab, with most events occrnTing within the first 6 months of therapy. 
Pe1manently discontinue bevacizumab in patients with tracheoesophageal fistulae or any Grade 4 fistula. 
Lilnited infmmation is available on the continued use ofbevacizumab in patients with other fistulae. In 
cases of internal fistula not a1ising in the GI tract, discontinuationof bevacizumab should be considered. 
Wound healing complications:  Wound healing complications such  as wound dehiscence have been 
repo1t ed in patients receiving bevacizumab. In an analysis of pooled data from two trials in metastatic 
colorectal cancer, patients undergoing surge1y28-60 days before study treatment with 5-FU/LV plus 
bevacizumab did not appear to have an increased risk of wound healing complications compared to those 
treated with chemotherapy alone69. Surge1y in patien ts cun ently receiving bevacizumab is not 
recommended. No definitive data are available to define a safe inte1val after bevacizumab exposure with 
respect to wound healing risk in patients receiving elective surge1y; however, the estimated half life of 
bevacizumab is 21 days. Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
If patients receiving treatment with bevacizumab require elective major surge1y, it is recommended that 
bevacizumab be held for 4-8 weeks prior to the surgicalprocedure. Patients lmdergoing a major surgical 
procedure should not begin or resta1tbevacizumab until 4 weeks after that procedure (in the case of 
high-risk procedures such as liver resection, thoracotomy, or neurosurge1y, it is recommended that 
chemotherapy be restaited no eai·lier than 6 weeks and bevacizumab no eai·lier than 8 weeks after 
surge1y). 
Hem01Thage: Overa ll, grade 3 and 4 bleeding events were obse1ved in 4.0% of 1132 patients treated with 
bevacizumab in a pooled database from eight phase I, II, and III clinical trials in multiple tumor types 
(bevacizumab Investigator Brochure, October 2005). The hemonhagic events that have been obse1ved in 
bevacizumab clinical studies were predominantly tumor-as sociated hemonhage (see below) and lninor 
mucocutaneous hemorrhage. 
Tumor-Associated Hemorrhage: Major or massive pulmonaiy hemonhage or hemoptysis has been 
obse1ved p1imaii ly in patients with NSCLC. Life-threatening and fatal hemoptysis was identified as a 
bevacizumab-related adverse event in NSCLC trials. These events occrnTed suddenly and presented as 
major or massive hemoptysis. Among the possible 1i sk factors evaluated (including squamous cell 
histology, treatment with anti-rheumatic/anti-inflammato1ydrngs, treatment with anticoagulants, p1ior 
radiotherapy, bevacizumab therapy, previous medical histo1yof atherosclerosis, central tumor location, 
and cavitation of tumors drning therapy), the only variables that showed statistically significant 
con-elations with bleeding were bevacizumab therapy and squamous cell histology. 
 
GI hemonhages, including rectal bleeding and melena have been rep01ted in patients with CRC, and have 
been assessed as tumor-associated hemon hages. 
Tumor-associated hemon-hages we re also seen rarely in other tumor types and locations, including a case 
of CNS bleeding in a patient with hepatoma with occult CNS metastases and a patient who developed 
continuous oozing of blood from a thigh sarcoma with necrosis. 


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Mucocutaneus Hemonage: Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been 
seen in 20%-40% of patients treated with bevacizumab. These were most commonly NCI-CTC Grade 1 
epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any 
changes in bevacizumab treatment regimen. 
There have also been less common events of minor mucocutaneous hemonhage in other locations, such 
as gingival bleeding and vaginal bleeding. 
Reversible Posterior Leukoencephalopathy Syndrome: There have been rare repo1t s of beva.cizum ab- 
trea.ted patients developing signs and symptoms that are consistent with RPLS, a rare neurologic disorder 
that can present with the following signs and symptoms (amongothers):  seizures,  headache,  altered 
mental status, visual disturbance, or co1tical blindness, with or without associated hype1tension. Bra.in 
imaging is manda.to1y to confnm the diagnosis ofRPLS. In patients who develop RPLS, treatment of 
specific symptoms, including control of hype1et nsion, is recommended a.long  with discontinuationof 
beva.cizumab. The safety ofreinitia.ting beva.cizumab therapy in patients previously experiencing RPLS is 
not known67 68 
Congestive heait failure: In clinical trials CHF was observed in all cancer indications studied to date, but 
predominantly in patients with metastatic breast cancer. In the Phase III clinical trial of metastatic breast 
cancer (AVF2119g), 7 (3%) beva.cizuma.b-treated patients expe1ienced CHF, compared with two (1%) 
control a.nn patients. These events varied in seve1ity from a.symptomatic declines in left ventlicular 
ejection fraction (LVEF) to symptomatic CHF requiiing hospitalization and treatment. All the patients 
treated with bevacizumab were previously ti·eated with anthracyclines (doxombicin cumulative dose of 
240(360 mg/m2). Many of these patients also had p1ior radiotherapy to the left chest wall. Most of these 
patients showed improved symptoms and/or left venti·icula.r function following approp1ia.te medical 
therapy (Miller et al. 2005). 
In a randomized, Phase III trial of patients with previously untreated metastatic breast cancer (E2l 00), the 
incidence ofLVEF decrease (defined as NCI-CTC Grade 3 or 4) in the paclitaxel + bevacizuma.b aim was 
0.3% versus 0% for the paclitaxel alone ann 
No inf01mation is available on patients with preexisting CHF of New York Hea1t Association (NYHA) 
Class II- N at the time of initiating beva.cizumab therapy , as these patients were excluded from clinical 
trials. 
Prior anthracyclinesexposure and/or p1ior radiotherapy to the chest wall may be possible1isk factors for 
the development of CHF. Caution should be exercised before initiating bevacizumab therapy in patients 
with these risk factors. 
A Phase II tiial in patients with refract01y acute myelogenous leukemia repo1ted 5 cases of cardiac 
dysfunction (CHF or LVEF decrease to < 40%) among 48 patients treated with sequential cyta.ra.bine , 
mitoxanti·one, and bevacizuma.b. All but 1 of these patients had significant prior exposure to 
anthracyclines as well70. 
Two additional studies investigated concmTent administi·aiton of anthracyclinesand bevacizumab. In 
21 patients with inflammat01y breast cancer ti·eated with neoadjuvant docetaxel, doxombicin, and 


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bevacizmnab, no patients developed clinically apparent CHF; however, patients had asymptomatic 
decreases in LVEF to < 40%71. In a small Phase II study in patients with soft tissue sarcoma, 2 of the 
17 patients treated with bevacizumab and high-dose doxornbicin (75 mg/m2) developed CHF (one Grade 
3 event after a cumulative doxornbicin dose of 591 mg/m2 one Grade 4 event after a cumulative 
doxornbicin dose of 420 mg/m2 an additional 4 patients had asymptomatic decreases in LVEF72. 
Other studies in patients with valious tumor types and either a histo1yof anthracycline exposure or 
concomitant use with bevacizumab are ongoing. 
Patients receiving concomitant anthracyclines or with prior exposure to anthracyclines should have a 
baseline MUGA scans or echocardiograms (ECHOs) with a nmmal LVEF. 
Neutropenia: Increased rates of severe neutropenia, feb1ile neutropenia, or infection with severe 
neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic 
chemotherapy regimens plus bevacizumab in compatison to chemotherapyalone65 
Additional Adverse Events: See the bevacizumab Inves tigator Brochure for additional details regarding 
the safety expeti ence with bevacizumab. 
1.11 BevacizumabStudies in Head and Neck Carcinoma at the University of Pittsburgh 
A phase II study investigating the combination of pemetrexed and bevacizumab in recmTent or metas tatic 
HNSCC is ongoing with encouraging results (UPCI 05-002). 38 patients have been enrolled. In 29 
evaluable patients, 9 (31%) have had an objective response (3CR + 6PR), 16 (55%) SD, whereas 4 (19%) 
patients developed PD. The median TTP was 4.9 months and the median OS was approximately 12 
months. We had 6/38 (16%) grade 3-5 bleeding events (2 fatal), none after modificationsin eligibility 
were made to exclude patients with prior histo1yof tumor-related bleeding and do not allow retreatment 
after a first serious tumor-related bleeding. 
Another trial with cetuximab and bevacizumab (UPCI 05-087) has enrolled 32 patients. Prelimina1y 
results (ASCO 2009) suggest that the regimen is active and safe. Only one grade 3 bleedingin 32 patients 
has been observed. The objective response rate is 20%, the median PFS 2.8 months and the median OS 
8.1 months. 
In addition, another phase II randomized trial of radiation, cetuximab and pemetrexed with or without 
bevacizumab is ongoing, as well (UPCI 07-021). The regimen is feasible. No bleeding events have 
occutTed in 8 patients treated. 
1.12 Study Rationale 
Induction chemotherapy is gaining momentum in the management of locally advanced squamous cell 
cai·cinoma of the head and neck (SCCHN). The combination of docetaxel, cisplatin, and 5-FU (TPF) was 
supe1ior compared with PF in a Phase ill  clinical ttials73,_14   We have completed a Phase II clinical trial 
that showed that docetaxel, cisplatin, and cetuximab (TPE) is highly active and well tolerated as induction 
chemotherapy in SCCHN (Argitis et al. ASCO 2008; A6002). Preliminaiy survival results are very 
encouraging. 39 patients were enrolled and with median follow up 26 months the 2-yeai· PFS was 70% 
and the 2-year OS 84%.The combination of chemotherapy plus cetuximab is afready a standat·d treatment 


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. 
 
 
in rectment or metastatic SCCHN47 Therefore, TPE can be used as the platfonn for the addition of novel 
agents. 
EGFR and VEGF are among the most imp01tant and validated molecular targets in cancer therapy. The 
incorporation of novel targeted therapies to chemotherapy and radiotherapy is of particulru· interest in 
head and neck cancer, and may improve efficacy without significantly increasing toxicity. A Phase III 
trial of carboplatin/paclitaxel/bevacizumab with or without cetuximab in advanced NSCLC has been 
proposed by SWOG. Bevacizumab is ClllTently being inves tigated in SCCIIN with promising results. A 
Phase II study investigating the combination of pemetrexed and bevacizumab (UPCI 05-002) as well as a 
Phase II trial of cetuximab and bevacizumab (UPCI 05-087) in recU1Tent or metas tatic SCCHN ru·e 
ongoing at the University of Pittsburgh with encomaging results (ASCO 2008 and ASCO 2009). In this 
study, 32 have been afready emolled. There was only I patient with grade 3 hemo1Thage. The objective 
response rate is 20%, the median PFS 2.8 months and the median OS 8.1 months. 
In order to ftnther improve the efficacy of TPE and the rate of complete responses we propose to add 
bevacizumab to the TPE followed by XPE regimen we developed at the University of Pittsbmgh. Due to 
non-overlapping toxicities and based on om p1ior experience we anticipate that the regimen will be well 
tolerated. Moreover, we plan to obtain tumor biopsies and blood samples in the first cycle and evaluate 
the modulation of biomru·kers post combi nation thera py. Data from induction with TPE (presented at 
ASCO 2009) indicate the potential significance of cytokine levels in patient outcome. Also, we will 
evaluate the feasibility of subsequent conclllrnnt radiation, cisplatin, cetuximab and bevacizumab. 
Patients with stable disease in the prima1y could be considered candidates to smgical resection at the 
discretion of their physician, if the tumor is resectable. 
2 
OBJECTIVES 
 
2.1 
P1imar y 
To eva luate the rate of complete responses with induction with cisplatin, docetaxel, cetuximab and 
bevacizumab (TPE-A) in patients with locally advanced head and neck cancer. 
2.2 
Secondary 
• 
To evaluate se1um cytokines and to co1Te l ate wit h com p lete respo n se ra te post inductiontherapy. 
• 
To collect tumor tissue from pretreatment and post-treatment (optional) biopsies for biomarker 
studies on tumor tissue. We plan to investigate a panel of EGFR and angiogenesis biomarkers on 
Tissue Microrurnys (TMAs). 
• 
To evaluate the toxicities associatedwith induction TPE-A and  subsequent  concU1Tent  rad iation, 
cis platin , cetuximab and bevacizumab (XPE-A). 
• 
To evaluate the objective response rate post XPE-A, and the progression- free survival and 
overall survival and quality of life. 
 
3 
STUDY DESIGN 
 
3.1 
Induction Therapy (TPE-A) 


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3.1.1 
Treatment and Premedications 
Note: If a cycle is missed or a subject's treatment and/or testing days need to be rescheduled due to the 
subject's inability to comply with the study calendar (i.e., hospitalizations, business and vacation travel 
plans, illness, transp01tation issues, holidays, family emergencies, etc.), a window of± one (1) week is 
available for rescheduling of treatment and procedures per the discretion of the treating physician 
investigator, and as discussed with the principal investigator. 
 
Cycles will be repeated eve1y 21 days for 3 cycles 
Chemotherapy will be given on day 1 of a 21-day schedule and repeated eve1y 21 days for a total of 3 
cycles. The doses of docetaxel, cetuximab, and cisplatin will be calculated using the patient's actual body 
weight on day 1 of each cycle. Fluids given during the administration of docetaxel, bevacizumab and 
cetuximab is counted as pa1t of cisplatin pre-hydration. 
• 
Bevacizumab 15mg/kg IV, day 1 of each cycle. 
The bevacizumab dose should be delivered over 30 minutes as a continuous IV infusion 
prior to all chemotherapy infusions. Dexamethasone pre- and post-medication for 
docetaxel and as an antiemetic (see below). Dexamethasone decreases incidence and 
seve1ity and delays the onset of late-occm1ing fluid retention and may decrease the 
incidence and severity of acute hypersensitivity reactions. Dexamethasone 8 mg po bid x 3 
days, starting 12-24 hours before the planned docetaxel infusion has been an effective 
schedule. 
• 
Docetaxel 75 mg/m2 IV over 1 hour, day I. 
• 
In an effo1tto prevent a hypersensitivity reaction from cetuximab, all patients should be 
premedicated with diphenhydraminehydrochloride (Benadlyl) 50 mg (or an equivalent 
antihistamine) by IV given 30 minutes prior to the first dose of cetuximab.Premedication may be 
adlninistered p1ior to subsequent doses, but at the Investigator's discretion, the dose of 
diphenhyd·la1nine(or a similar agent) may be reduced. 
• 
Cehlximab 400 mg/m2 IV over 1201ninutes on day 1 of cycle 1 ONLY. 
• 
Cehlximab dose will be 250 mg/m2 IV over 60 1ninutes weekly on ALL subsequent 
adlninistrations(days 8 and 15 of cycle 1 and days 1,8,15 of cycles 2 and 3). 
• 
Cisplatin 75 mg/m2 IV over 1-2 hours, day 1. It is strongly recommended that patients receive G- 
CSF sta1ting on day 2 of each TPE-A cycle. If this is not possible, patients will receive 
prophylactic ciprofloxacin 500 mg twice daily for 10 days, on days 5-14. 
• 
Furosemide will be given as needed. 
• 
Antiemetic therapy, acute and delayed, includingdexamethasone and serotonin receptor 
antagonists, for 4 days is recommended. Aprepitant should be used with caution due to the 
possibility of a d11.1g- dlu  g  interaction with docetaxel via CYP3A4 pathway. 
The following hydl·ation regimen is recommended: 
• 
Cisplatin will require aggressive hydl·ation. Any preexisting dehydl·ation should be coITected. Pre- 
cisplatin hydration will consist of 1 L NS administered over 2 hours (taking into account the fluid 
volumes received from prior dlug administration). Mannitol 12.5 g IV bolus can be given just 
before or concun ently with cisplatin. Pre-cisplatin hydl·ation can occur while patient is receiving 


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infosions of bevacizmnab, cetuximab, docetaxel. Hydration must not occur in the same IV line as 
chemotherapy (i.e. use patient' s other ann). 
• 
Cisplatin will be administered in 500 -1000 cc of IV fluids over 1-2 hours and following adequate 
hydration and the establishment of adequate urina1youtput. 
• 
Post cisplatin hydration will consist of 1 L ½ NS + 30 meq KCL/L over 2 hours (mannitol 25 g 
IV may be added). 
3.1.2 
Cet11ximab Administration 
In an effo1t to prevent an infosion reaction, all patients should be premedicated with diphenhydra1nine 
hydrochloride 50 mg (or an equivalent antihistamine) by IV given 30-60 minutes prior to the first dose of 
cetuximab. Premedication may be administered prior to subsequent doses, but at the Investigator's 
discretion, the dose of diphenhydramine (or a similar agent) may be reduced. 
The initial dose of cetuximab is 400 mg/m2 intravenously administered over 120 minutes, followed by 
weekly infosions at 250 mg/m2 IV over 60 minutes. The infosion rate of cetuximab must never exceed 5 
mL/min. Patients must be continuously observed dming the infosion for signs of anaphylaxis. 
Patients will be closely monitored for treatment-related adverse events, especially infosion reactions (see 
management of cetuximab adverse events). 
For the duration that patients are on study therapy, adverse event monitoring will be done continuously. 
Patients will be evaluated for adverse events at each visit and are to be instmcted to call their physician to 
repmt any clinically significant adverse events between visits. 
3.1.3 
Bevaciz111nab Administration 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodimn Chloride Injection, USP. 
Administration will be as a continuous IV infosion. Anaphylaxis precautions should be obse1ved during 
study dmg administration. It is not necessaiy to con-ect dosing based on ideal weight. 
Initial and all subsequent doses will be delivered over 30 minutes. If a subject expe1iences an infusion- 
associated adverse event, he or she may be premedicated (aceta1ninophen, diphenhydramine, steroids or 
other medications given for symptom control) at the investigators discretion, p1io r to the next sn1dy dmg 
infosion; however , the infosion time may not be decreasedfor the subsequent infosion. Surge1y for 
3.1.4 
Selected Patients after Induction Therapy and as Salvage 
Patients will be evaluated after completion of induction therapy with PET/CT. Patients with SD in the 
primaiy could be considered candidates for surgical resection at the discretion of their treating physicians, 
if the tumor is resectable. Salvage surge1y should be perfonned if there is progressive disease or residual 
disease in the prima1y at the end of therapy . At least 4 weeks should elapse between last bevacizumab 
dose and any surge1y. Neck dissection should be considered, if there is high probability for residual 
disease in the neck after completion of chemoradiotherapy (>8 weeks later). 
3.2 
Concun ent Radiothe.-apy, Cisplatin , Cetu ximaband Bevacizumab (XPE-A) 
Bevacizumab, 15 mg/kg IV over 30 minutes (if this infosion rate was well tolerated), eve1y 3 weeks until 
completion of radiation; 


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Followed by: 
Cetuximab, 250 mg/m.2 IV over 60 minutes, weekly x 7-8 weeks dU1i.ng days of radiation (Benadty l 
premedication 30-60 minutes prior to cetuxim.ab infusion as required, see 3.1.1); 
Cisplatin, 30 m.g/m.2 over 1 hom, weekly x 7-8 weeks dming days of radiation (the same day that 
cetuximab is given). 
Patients who receive radiation over 8 weeks m.ay receive an 8th dose of cisplatin and cetuxim.ab. 
Radiation therapy 70 Gy/200 cGy/daily, 5 days/week (see 3.3): 
• 
One hom of observation should elapse before staiting cisplatin (dming that pe1iod of time 
patients will be receiving pre-cisplatin hydt·ation). 
• 
Bevacizumab will be given first followed by cetuximab (when it should be given) and finally 
cisplatin on the same day (only on days that radiation is administered). 
• 
Radiation will be administered following cisplatin adtninistration. 
 
Radiotherapy will sta1t approximately 3-4 weeks after Cycle 3, Day 1. 
 
Administrationof Cisplatin 
Cisplatin will require aggressive hydt·ation. Any preexisting dehydt·ation should be co1Tec ted. The 
following hydration regimen is recommended: 
• 
Pre-cisplatin hydration will consist of 1 L NS adtninistered over 2-3 homs (taking into account 
the fluid volumes received from prior dtug administration). Mannitol 12.5 g IV bolus can be 
given just before or concmrently with cisplatin. 
• 
Cisplatin will be adtninistered in 500 -1000 cc of IV fluids over 1-2 homs and following adequate 
hydration and the establishment of adequate mina1y output. 
• 
Post cisplatin hydt·ation will consist of 1 L ½ NS + 30 m.eq KCL/L over 2-4 hours (mannitol 25 g 
IV m.ay be added). 
Furosemide will be given as needed. 
 
Antiemetic therapy, acute and delayed, including dexam.ethasone and serotonin receptor antagonists is 
recoIIlIIlended . 
3.3 
Radiation Thernpy 
 
3.3.1 
Physical Factors 
• 
Equipment: Lineai·acce lerator with appropriate photon and electron energies for supplemental 
boosting to the nodes. 
• 
Photon energies of 1.25 to 6 MV and/or approp1iate electron energies for boosting the nodes are 
allowed. Photon energies > 6 MV may be utilized when appropriate to boost tai·get loca lized 
centra lly. 
• 
Minim.um. treatment distance must be =::>: 80 
cm 
SSD 
(or 
SA  D for isocentiic techniques). 
 
3.3.2 
Localization Requiremenst 


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3.3.2.1 
Simulation 
Simul ation of all fields is mandato1y. Patients must be reproducibly immobilized. Radio-opaque markers 
should be used to delineate the extent of nodal disease and whenever possible, the prima1ytumor, if 
conventional treatment planning is used. The use of customized Ce1rnbend blocks is recommended to 
shape the field and limit dose to nonnal strnctures. Use of multileaf collimator to shape the field is 
suggested. For CT simulation, I. V. contrast is recommended and the data should be acquired using 3 mm 
slice width and spacing using the spiral mode of scanner. 
3.3.2.2 
Verification 
 
Check films should be weekly. Beam po1tal films must be obtained to each field. Electron fields utilized 
for supplemental nodal boosting must be ve1ified by po1tal ve1i fication, simu lation, or diagram. 
3.3.3 
RadiationDose 
Treatment to the p1i mruy tumor and upper neck will be given at 2 Gy/fraction once each day, five days a 
week. A total dose of70 Gy/35fraction/7weeks will be delivered. Fields must be reduced to exclude the 
spinal cord at 36 Gy with dose calculated in the central plane. The entire neck must be inadiated to a total 
dose of at least 46- 50 Gy (even in NO stage) at anatomic levels of lymph nodes usually 2-4 cm beneath 
the skin surface. Clinically positive neck nodes should also receive a dose of 70 Gy/35 fractions given 
continuously for 7 weeks. An electron beam should be used to supplement the dose to the posterior 
cervical chain nodes after the spinal cord has been shielded. Hence, the total dose to the p1imruy tumor 
and clinically positive nodes will be 70 Gy/35 continuous fractions/7 weeks. The ante1ior lower neck will 
be trea ted at 2 Gy/fraction once a day (3 cm depth) from the ante1ior to a total dose of 46-50 Gy/25 
continuous fractions (if clinically negative) in 5 weeks. The maximum dose pe1mitted to the spinal cord 
will not exceed 45 Gy as dete1mined by a separate off-axis point dose calculation. 
Patients who undergosurge1y post TPE-A can strut XPE-A within an interval of 4-10 weeks after surge1y 
(6 weeks recommended). In that case the total postoperative radiation dose will be up to 66 Gy. 
3.3.4 
Target Volume Irradiation and Radiation Doses 
A combination of lateral opposing fields is recommended for the treatment of the prima1y tumor site and 
upper neck. A single anterior AP field will be used to treat the lower neck below the fields of the p1i ma1y 
tumor/upper neck. When there are clinically involved lymph nodes in the lower neck, an additional 
posterior (PA) field may be necessruy to deliver a supplemental dose to the positive nodes. All fields must 
be treated at each treatment session. The upper and lower fields should be matched using a "three 
dimensional" technique (i.e., approp1iate rotation of the treatment table and appropriate angulation of the 
collimator or beam split technique). However, if such a three-dimensional match is not possible, the upper 
neck and supraclaviculru· fields may be abutted at the skin. The latter case, a small block should be placed 
either in the lower lateral position in the upper neck fields, or in the midline of the ante1ior 
supraclav icular field (wh icheve r is approp1iate and does not block tumor) to the shield ru·eas of potent ial 
over lap of dive rgin g beams over the spinal cord. 
3.3.5 
Upper Neck Primary Volume 
• 
The p1ima1y treatmen t fields should encompass the p1ima1y n1mor and/or suspected lymph node 


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CONFIDENIATL 
 
 
 
 
disease in the upper neck using the shrinking field technique as follows: 
• 
The initial target volume should include the primruy tumo r, pos iti ve nodes w ith an approximately 
3.0 cm mru·gin and the next echelon of uninvolved lymphatic nodal drainage sites to a dose of 50 
Gy. Included in the target volume is the first field reduction occmTing off the sp inal cord at 36 
Gy. 
• 
The secondfield reduction will occur at 50 Gy and continue to 60Gy with the new tat·get volume 
encompass ing the p1ima1y tumor and known areas of nodal disease with at approximately 2.0 cm 
margm. 
• 
The third and final field reduction will occur at 60 Gy and continue to 70 Gy with the new target 
volume encompassing the prima1ytumor and known ru·eas of nodal disease with at approximately 
1.0 cm margin. 
As a general mle, both ipsilateral and contralateral posterior cervical nodal chain and the adjacent 
echelon of uninvolvedlymphatic nodal drainage sites will be treated to a dose of 46-50 
Gy/5 weeks. 
3.3.6 
Lower Neck Volume 
• 
A single lower neck field will be used to treat the lower neck and the supraclavicular fossae. 
When there is (are) positive node(s) in the lower neck, an additional poste1i or field may be 
necessa1y to deliver a supplemental dose to the positive node(s). The boost dose should not 
exceed 70 Gy. 
• 
The lower border of the lower neck field will be just below the clavicular head with appropriate 
mru·gins when there ru·e pos iti ve nodes in the Supraclavicular fossa. The lateral borders of the 
lower neck field will extend to the intersection of the stemocleidomastoid muscle and the 
clavicle. 
• 
For all patients with clinically positive nodes greater than 6 cm, or with clinically positive 
supraclaviculru· nodes , a med iast ina l "T " field may be used. The lateral limbs of the T field will 
extend below the clavicular heads with mru·gin, and the central po1tion of the field extends 5 cm 
more inferiorly to include the upper mediastinum. 
3.3.7 
Boost Doses 
Additional boost doses may be given through reduced field to persistent tumor and/or clinically positive 
nodes, or to compensate for significant intem1ptions in radiation therapy treatments (i.e., > 57 elapsed 
days). The additional boost dose should not exceed 4 Gy (i.e., 74 Gy maximum). The spinal cord must be 
excluded from any boost field. 
3.3.8 
Dose Calculations 
Photon Beam Portal An angements 
• 
Dose specification for two parallel-opposed coaxial equally weighted beams is to be on the 
central ray at mid-separation of the beams. 
• 
Dose specification for two or more intersecting beams is at the intersection of the central ray of 
the beams. 
• 
For other complex treatment rurnngemen ts, dose is specified at the center of the clinical tru·get 
volume. 


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Note: There may be several target volumes. 
• 
For a single anterior AP lower neck field, the prescribed does will be delivered at a depth of 3.0 
cm as determined by an off-axis "supraclavicular point". When AP-PA fields are used to treat the 
lower neck, the dose shall be prescribed at the mid-separation of the two beams along the central 
ray. 
3.3.9 
Isodose Distributions 
Isodose distribution at central axis is required. All trnatment volumes and critical stmctures should be 
indicated. Complete isodose curves are required. Attempts should be made to keep the dose variation 
within the planning target volume to be within +/- 5% of the target dose. 
3.3.10 Electron Beam Dose Specifications 
The target dose shall be prescribed at the depth of maximum dose. The energy and field size shall be 
chosen so that the target volume is encompassed within 90% of the presc1ibed dose. 
3.3.11 Time and Dose Modifications 
• 
Treatment intem.1ptions  are   strongly discouraged. Treatment breaks must be clearly indicated in 
the treatment record when they occur. If the  total treatment  inte1ruptions exceed  ten  treatment 
days, the treatment will be considered  a  protocol  deviation. The intenuption of  radiation therapy 
for grade 4 mucositis/denn atitis/dysphagia is at the discretion of the treating oncologist. 
• 
The maximum permitted spinal cord dose is 45 Gy. 
• 
Mandibular osteoradionecrosis will rarely occur if pretreatment dental evaluation is conducted 
prior to radiation therapy treatment. Pretherapy extractions of badly diseased teeth should be 
canied out with conservation of restorable teeth when possible. If an extraction site in the 
mandible has to be included in the ilrndiated field, 10 to 14 days should be allowed for healing 
before the initiation of ilrndiation. 
3.3.12 RadiotherapyGuidelines/IMRT 
Intens ity Modulated Radiation (IMRT) is recommended in this study. 
 
3.3.12.1 
Proposed Radiotherapy Guidelines 
• 
 All patients will have immobilization devices with treatment planning based on Computerized 
Tomography (CT) information in treatment position. The CT slice thickness through target will 
be 3 mm. 
• 
CT and Magnetic Resonance Imaging (MRI) data will be used to define the vaiious targets and 
contour normal stmctures. MRI infonnation will be used when indicated. Image fusion will be 
used to relate CT/MRI data when necessaiy. 
• 
The field sizes and atTangements will be at the discretion of the attending Radiation Oncologist. 
ICRU 50 guidelines will be used for vaiious Tumor and Target Nomenclature: 
o 
The Gross Tumor Volume (GTV): All gross disease detemlined from clinical 
exatmnation and radiographic studies (CT/MRI). 
o 
The Clinical Tai·get Volume (CTV): The ai·ea that potentially contains microscopic 
disease. Lymph node groups at risk of microscopic disease will be outlined as pait of 


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corresponding CTV. The margin between each GTV and co1Tesponding CTV can vruy 
from 0.2 cm to 2.5 cm depending upon the proximity to the critical and uninvolved 
strnctures. 
o 
The Planning Tru·get Vol ume (PTV): Provides a margin around CTV to compensate for 
internal motion and set up errors. Typically a 5 mm margin may be used around CTV. 
 
3.3.12.2 
Radiation Target and Dose Specifications 
The following is the definition of tru·gets and their dose specifications. 
• 
Prima1y T ru·get (PTV3): Includes PTV's of prima1y tumor and the lymph nodes containing 
disease. The dose will be ?.70 Gy at 2 GY/ fractions. 
• 
Secondruy Target (PTV2): Includes PTV's of area at moderate to high1isk of microscopic disease 
i.e. first echelon nodes. The dose will be ?. 60 Gy. This is at the treating physican discretion. 
• 
Te1tiruy T ru·get (PTV,): Includes PTV' s of areas that are at low 1isk of microscopic disease i.e. 
second echelon lymph nodes. The dose will be approximately ?. 46-50 Gy. 
 
Low Neck: The midjugulru·, lo w ju gular, and supraclaviculru·nodes can be treated with IMRT or 
alternatively with an AP field that is beam split to the IMRT fields. Dose Volume Histograms(DVH) will 
be generated for each plan. Radiation doses will be as outlined above. 
Treatment Planning: Either fo1ward or inverse planning can be used in order to achieve the following: 
• 
The radiation dose will be prescribed to the isodose line that encompasses 95% of PTV. 
• 
No more than 15% of the PTV will receive >110% of the prescribed dose. 
• 
The maximum dose within PTV does not exceed >25% of the prescribed dose. 
• 
No more than 1% of the tissue outside PTV will receive >110% of the prescribed dose. 
• 
No more than 1% of any PTV will receive< 93% of the prescribed dose. 
• 
Tissue heterogeneity co1Tection is manda to1y. 
• 
The planning priorities include critical normal stmcture constraints followed by prescription 
goals. 
 
No1mal Tissues : The appropriate n01mal organs will be contoured. Dose Volume Histograms (DVH) will 
be generated. An attempt will be made to keep the maximum radiation doses to the following organs as 
follows: 
Brain Stems: 
Optic Nerve/Chiasm: 
Spinal Cord: 
Mandible/TM Joint: 
La1ynx 
54Gy 
55 Gy 
45 Gy 
70 Gy or 1 cc of the PTV not to exceed 75 Gy 
70Gy 
 
Pru·otid Glands: Attempt will be to achieve mean dose :'.S 26 Gy in at least one gland or at least 20cc of the 
combined volume of both parotid glands will receive < 20 Gy or at least 50% of the gland will receive < 
30 Gy (should be achieved in at least one gland). 


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Other No1mal Stmcrures: Submandibular /sublingual glands, inner and middle ears, eye, lens will be 
considered low priority. The aim should be to decrease the doses as much as possible without 
compromising target. 
Toxicities, and all interventions for toxicity, must be recorded on the data forms. 
For patients who have undergone surgery without macroscopic residual disease a total radiation 
dose of up to 66 Gy will be administered (as postoperative treatment). 
3.4 
Supportive Care 
• 
All supp01tive measure s consistent with optimal patient care will be given throughout the srudy. 
Aggressive oral and skin care and analgesics are recommended. 
• 
Antiemetics: Patients will receive antiemetic therapy as recommended in the treatment plan. 
• 
Concomitant Dmgs 
The prophylactic use of G-CSF is recommended during induction chemotherapy (i.e. Neulasta on 
day 2 of each induction TPE-A cycle or Neupogen on days 2-11). If G-CSF cannot be 
administered for any reason, prophylactic antibiotics (e.g. ciprofloxacin 500 mg BID will 
be administered on days 5-14 of each cycle of TPE-A). The use of G-CSF is not allowed 
dming radiotherapy. 
The use of erythropoietin is not allowed. 
No other antitmnor agents will be given dming protocol therapy. 
o 
The use of amifostine is not pe1mitted. Piloca rpine (Salagen) is not encouraged dming 
treatment but is allowed. If used, it should be recorded in the treatment fo1ms. 
3.5 
Gastros tomy Tubes 
Prophylac tic placemen t of a gastrostomy rube before any treatment begins is recommended but is at the 
discretion of the treating physician. It is strongly recommended in patients with significant dysphagia and 
weight loss of >10-15% at baseline or poor overall nutlitional starus. 


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4 
SAFETY REPORTING OF ADVERSE EVENTS 
 
4.1 
Definitions 
Adverse event (AE) means any untoward medical occunence in a patient or subject administered a 
medicinal investigational dmg; the untoward medical occunence does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnonnal laborato1yfinding, for example), symptom, or disease temporally associated with 
the use of an investigationalmedicinal product whether or not it is considered to be related to the 
medicinal investigational dtug. This includes any newly occuni ng event, or a previous condition that has 
increased in severity or frequency since the adtninistration of study drng. 
An abno1mal laborat01y value will not be assessed as an AE unless that value leads to discontinuation or 
delay in treatment, dose modification, therapeutic inte1vention, or is considered by the investigator to be a 
clinically significantchange from baseline. 
 
Serious Adverse Event Definition 
 
Se1ious AE (SAE) means any untoward medical occunence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. (The te1m "life-threatening"in the definition of "se1ious" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event, which 
hypothetically lnight have caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of present hospitalization (see cla1ification 
in the paragraph below on planned hospitalizations). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
dismption of a person's ability to conduct n01mal life functions. 
• 
Is a congenit al anomal y/birth defect. 
• 
Is a medically important event that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the patient or may require inte1vention to prevent one of the 
other outcomes listed in the definition above, or involves suspected translnission via a medicinal 
product of an infectious agent. Examples of such medical events include allergic bronchospasm 
requiting intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the developmentof dmg dependency or  dtug 
abuse; any organism, vims, or infectious pruticle (e .g., prion prote in translnitt ing Translnissible 
Spongifo1mEncephalopathy), pathogenic or non pathogenic, is considered an infectious agent. 
 
Cla1ification should be made between the te1ms selious and severe because they ARE NOT synonymous. 
The te1m seve re is often used to describe the intensity (sevetity) of a specific event (as in lnild, moderate, 
or severe myocardial infru·citon);  the event itself, however, may be ofr elatively minor medical 
significance (such as a severe headache). This is NOT the same as se1ious, which is based on 
patient/event outcome or action c1iteria desc1ibed above and is usually associated with events that pose a 
threat to a patient' s life or fimctioning. A severe AE does not necessa1liy need to be considered serious. 
For exrunple, persistent nausea of several hours duration may be considered severe nausea but not an 


CTRC at UTHSCSA 
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CONFIDENTIAL 
 
 
 
 
SAE. On the other hand, a stroke resulting in only a minor degree of disability may be considered mild 
but would be defined as an SAE based on the above noted criteria. Se1iousness (not seve1ity) serves as a 
guide for defining regulato1y repo1ting obligations. 
 
Unanti cipated Problem Involving Risk to Subjectsor Others (UPIRSO) 
 
Unanticipated problem involving lisk to subjectsor others includes any incident, expelience or outcome 
that meets all of the following criteria: 
(1) 
unexpected (in te1ms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRE-approved research protocol and 
info1med consent document; and (b) the characteristics of the subject population being studied; 
(2) 
related or possibly related to paiticipation in the reseai·ch; and 
(3) 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social ha1m) than was previously known or recognized. 
Procedures for Recording and Rep01ting Adverse Events, Se1ious Adverse Events and UPIRSOs 
 
All AEs spontaneously repo1ted by the patient and/or in response to an open question from study 
personnel or revealed by obse1v ation, physical examination, or other diagnostic procedures will be 
recorded on the approp1iate page of the CRF. Any clinically relevant deterioration in laborat01y 
assessments or other clinical finding is considered an AE and must be recorded on the approp1ia te pages 
of the CRF. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as one comprehensive event. 
 
All SAEs, se1ious pretreatment events and UPIRSOs (as defined in Section 4.3) must be rep01ted by the 
investigator to the data safety monitoring boai·d (DSMB#2) (See Section 15) in addition to Genetech (See 
Appendix I) or designee (contact inf01mation provided below) by faxing the institutional SAE/UPIRSO 
Fo1m within 1 worki ng day after becoming aware of the event. In addition notification via facsimile to 
Genetech (See Appendix I) is required within 1 working day after becoming aware of the event. All 
SAEs, se1ious pretreatment events and UPIRSOs must be rep01ted whether or not considered causally 
related to the study mug or study procedures; however, se1ious pretreatment events that ai·e directly 
related to disease progression, and unrelated to study procedures, ai·e not required to be rep01ted . SAE 
report info1m ation and  the dataprovided on the CRF must match.  All SAEs should be monitored until 
they ai·e resolved or are cleai·ly dete1mined to be due to a patient's stable or chronic condition or 
intercmi:ent illness(es). The SAE rep01t  must include event te1m(s), se1ious c1ite1i a, and  the investigator 
or sub-investigator's dete1mination of both the intensity of the event(s) and the relationship of the event(s) 
to study drng adininistration. 
 
Planned hospital adinissions or surgical procedures for an illness or disease that existed before the patient 
was enrolled in the tiial are not to be considered AEs unless the condition dete1iorated in an unexpected 
manner dming the tiial (e.g., surge1y was perfo1med earlier or later than planned). 


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For both serious and nonserious AEs, the investigator must determine both the intensity of the event and 
the relationship of the event to study drng administration. For serious pretreatment events, the 
investigator must determine both the intensity of the event and the relationship of the event to study 
procedures. 
 
Intensity for each AE, including any lab abnotmality, will be dete1mined using the NCI CTCAE, Version 
4.0, 28 May 2009. 
 
Monitoring of Adverse Events and Pe1iod of Observation 
 
AEs, both nonse1ious and serious (which include all deaths), will be recorded on the CRFs. AEs will be 
repmted from dosing on Cycle 1, Day 1 through 30 days after the last dose of study dtug. Serious 
pretreatment events will be repo1ted from the time of the signing of the consent up to first dosing on 
study; however, serious pretreatment events that are directly related to disease progression, and unrelated 
to sn1dy procedure,s are not required to be reported. SAEs will be repotted from the first dose of study 
dtug up to and including the 30 days after administration of dtug in the study. All SAEs (which include 
all deaths) must also be reported to Genentech (See Appendix I) in addition to the Data Safety Monit01ing 
Committee (DSMC). All SAEs should be monitored until they are resolved or are clearly detennined to 
be due to a patient's stable or chronic condition or intercunent illness(es). 
Any SAE that occurs at any time after completion of the study and the designated follow-up petiod that 
the investigator considers to be related to study dtug must be repmted to Genentech and the DSMB. 
 
This is an investigator-initiated study. The ptincipal investigator, Anand Kamad, MD, who may also 
sometimes be referred to as the sponsor-investigator, is conducting the study and acting as the sponsor. 
Therefore, the legal/ethical obligations of the ptincipal investigator include both those of a sponsor and 
those of an investigator. In the event that this is a multisite study, the sponsor-investigator is responsible 
to ensure that the SAE repmts are sent to Genentech and FDA from all sites patticipating in the study. 
Subinvestigators must repott all SAEs to the sponsor-investigator so that the sponsor-investigator can 
meet his/her foregoing repmting obligations to the IRB, Genentech and FDA, unless othe1wise agreed 
between the sponsor-investigator and subinvestigator(s). The IRB, Genentech and FDNJllay request 
follow-up infotmation to a repo1ted SAE, which the sponsor-investigator will be responsible for 
providing. 
Sponsor-investigator must also provide Genentech with a copy of all communications with applicable 
regulato1y auth01ities related to the sn1dyor study dtug(s), including, but not limited to, telephone 
conversation logs, as soon as possible but no later than 5 calendai· days of such communication. 
 
Genentech will send to the sponsor-investigator a monthly listing of the SAE repmts received for SAE 
verification. Sponsor-investigator will be responsible for fotwarding such repmts to any 
subinvestigator(s). 


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CONFDI ENTIAL 
 
 
 
 
4.2 
Reporting to IRB 
These events requi1ing rep01ting to the FDA also must be repo1et d by the Investigator to the approp1iate 
Institutional Review Board (IRB). The IRB cunently requires the repo1ti ng of serious (including life- 
threatening and fatal) adverse events that are unanticipated (i.e., unexpected) and felt to be associated 
with (i.e., possibly related or related to) the research intervention(s). Fatal and life-threatening adverse 
events meeting these c1ite1i a are to be rep01ted to the Univers ity IRB within 24 homs of the investigator- 
sponsor becolning aware of this infonnation. Se1ious adverse events meeting these c1iteria are to be 
reported to the University IRB within 5 days of the investigator-sponsor becolning aware of this 
infonnation. 
MedWatch 3500a Reporting Guidelines: 
In addition to completing approp1iate patient demographic and suspect medication infonnat ion, the repo1t 
should include the following info1mation within the Event Desc1iption (section 5) of the MedWatch 
3500a fonn: 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol desc1iption (and number, if assigned) 
• 
Desc1iption of Event, Seve1ity, Treatment and Outcome (if known) 
• 
Suppo1tive laborat01y res ults and diagnostics 
• 
Investigator's assessment of the relationship of the adverse event to each investigational product 
and suspect medication 
Follow-up information: 
Additional informationmay be added to a previously sublnitted report by any of the following methods: 
 
• 
Adding to the original MedWatch 3500a rep01t and sublnitting it as follow-up 
• 
Adding supplemental summa1y information and sublnitt ing it as follow-up with the 01iginal 
MedWatch 3500a fo1m 
• 
Summarizing new info1mation and faxing it with a cover letter including subject identifiers (i.e. 
D.O.B. initial, subject number), protocol desc1iption and number, if assigned, suspect drug, b1i ef 
adverse event desc1iption, and notation that additional or follow-up inf01mation is being 
sublnitted (The subject identifiers are imp01tant so that the new information is added to the 
con ect initial repo1t ) 
 
Occasionally Genentech may contact the reporter for additional info1mation, claii fication, or cmTent 
stat us of the subject for whom and adverse event was repo1ted. 
Assessing Causality: 
Investigators ai·e required to assess whether there is a reasonable possibility that bevacizumab caused or 
contributed to an adverse event. The following general guidance may be used. 
: if the temporal relationship of the clinical event to bevacizumab adlninistration makes a causal 
relationship possible, and other diugs, therapeutic inte1ventions or underlying conditions do not provide a 
sufficient explanation for the obse1ved event. 


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CONFIDENTIAL 
 
 
 
 
No: if the temporal relationship of the clinical event to bevaciZUII1ab administration makes a causal 
relationship unlikely, or other chu gs , therapeutic interventions or underlying conditions provide a 
sufficient explanation for the observed event. 
 
 
5 
STUDY SUBJECTS 
 
5.1 
Eligibility Cii teria 
• 
Patients with AJCC 7th edition stage III-IVB head and neck cancer, aU sites, including unknown 
primaiy tumors. 
• 
Prior to ent:J.y in the  study the resectability and alternative treatment options for each patient will 
be determined by a team composed of an Eai·, Nose, and Throat Surgeon, a Radiation Oncologist 
and a Medical Oncologist. Stage determination, optimal local t:J.·ea t:J.nent , and its timing according 
to this protocol will be detennined at this evaluation. The unequivocal demonst:J.·at ion    of   di  stan   t 
metastasis (M1) confers ineligibility. 
• 
Histologically or cytologically confinned diagnosis of squainous cell or poorly differentiated 
carcinomas, or WHO types I-III of the nasopha1ynx. 
• 
UnidimensionaUymeasurable disease is required (RECIST 1.1). 
• 
No prior chemotherapy, biologic/moleculai·tai·geted therap y (including any prior therapy which 
specifically and directly tai·gets the EGFR pathway), or radiotherapy for head and neck cancer. 
• 
Prior surgical therapy will consist only of incisional or excisional biopsy, and organ spai·ing 
procedures such as debulking of ailway compromising tumors or neck dissection in a patient with 
an existing prima1y tumor. Any non-biopsy procedure must have taken place > 4 weeks but < 3 
months of initiating protocol treatment. 
• 
ECOG perfonnance status 0-1. 
• 
Age of :2:18 y ears. 
• 
Inf01med consent must be obtained from all patients prior to beginning therapy. Patients should 
have the ability to understand and the willingness to sign a written informed consent document. 
• 
All patients should have their tumor tissue  tested  for  HPV  (in  situ  hybridization  and/or  p16 
staining by immunohistochemist:J.y ) , and 
re sults mu s t be known prior to study ent:J.y, and w ill 
consent to have available archival  tumor samples,  unstained slides or  blocks from previous 
diagnostic or therapeutic procedures submitted for c01Telative studie s, including assessment of 
tai·get molecule s EGFR, VEGF and related biomarkers. Also, patients must agree to submit blood 
samples for co1Telative stud ies at least at baseline . 
• 
Abso lute neu troph il count :2: 1 500  / µl , P latelet 
co u nt :2: 100 ,000 / µl 
• 
Creatinine clearance 60 ml/min or higher calculated using the Cockcroft-Gault formula: 
Calculated Creatinine Clearance= O40-age) X actual body wt (kg) 
72 X sernm creatinine 
Multiply this number by 0.85 if the patient is female 
• 
Total bililu bin within nonnal limits and AST/ALT less than 3 times the upper limit ofnonnal. 
• 
U1ine dipstick must be < 0-1+ within 2 weeks (14 days) of randomization. If urine dipstick result 
is > 1+, a calculation of U1ine Protein Creatinine (UPC) ratio is requil·ed. Patients must have a 


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CONFIDENIATL 
 
 
 
 
UPC ratio < 1.0 to patticipate in the study. 
NOTE: UPC ratio of spot mi ne is an estimation of the 24-mi ne protein excretion - a UPC ratio of 
I is roughly equivalent to a 24-hour urine protein of l gm. UPC ratio is calculated using 
one of the following fo1mula: 
o 
[mi ne protein]/[urine creatinine] - if both protein and creatinine ai·e rep 01ted in mg/DI 
o 
[(urine protein) x 0.088]/[urine creatinine] - if urine creatinine is repo1ted in mmol/L 
• 
Patients with a prior histo1y of squamous cell or basal carcinoma of the skin or in situ cervical 
cancer must have been curatively treated. Patients with a histo1y of other prior malignancy must 
have been h·eated with curative intent and must have remained disease-free for 3 years post 
diagnosis. 
• 
Patients may not be receiving any other investigational agents. 
5.2 
Exclusion Criteria 
• 
Histmy of severe allergic reactions ath·ibuted to docetaxel or compounds of similar chelnical or 
biologic composition to docetaxel, or other drugs fmm ulated with polysorbate 80. 
• 
Plior severe infusion reaction to a monoclonal antibody or known hypersensitivity to any 
component of bevacizumab 
• 
Unconh·olled intercmTentillness incl uding , but not limited to, ongoing or active infection or 
psychiatric illness/social situations that would lilnit compliance with study requirements. 
• 
All patients will have a baseline EKG. If abn01m alities consistent with active coron aiy ait e1y 
disease ai·e detected , the patient will be refen ed to a cai·diologist for approp1iate evaluation and 
management prior to treatment on study 
• 
No patients with significant baseline senso1y or motor neurologic deficits (> grade I neuropathy) 
will be treated on this study. 
• 
Because patients with immune deficiency ai·e at increased1isk of lethal Infections when h·eated 
with matTow-suppressive therapy , HIV-positive patients ai·e ex cl uded from the study. Appropriate 
studies will be unde1taken in patients with HIV and those receiving combination anti- reh·oviral 
therapies when indicated. 
• 
Patients with HPV positive tumors (Pl 6+ by immunohistochelnishy and/or HPV+ by in situ 
hybridization) AND smoking histmy =<10 pack-years 
• 
Inadequately conh·olled hype1tension (defined as systolic blood pressure >150 mmHg and/or 
diastolic blood pressure > 100 mmHg) 
• 
Pi·ior histo1yof hype1tensive c1i sis or hype1tensive encephalopathy 
• 
New York Hea1t Association (NYHA) Grade II or greater congestive hea1tfailure (see Appendix 
F) 
• 
Histo1y of myocardial infai·ction or unstable angina within 12 months prior to Day I 
• 
No histmy of sh·oke or h·ansient ischelnic attack within 6 months p1ior to Day I 
• 
Significant vascular disease (e.,g. ao1t ic anemy sm, requiting surgical repait·or recent pelipheral 
a1te1ial thrombosis) within 6 months p1ior to Day I 
• 
Histmy of hemoptysis ( 1/2 teaspoon of b1ight red blood per episode) within I month prior to 
Day I 


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CONFDI ENTIAL 
 
 
 
 
• 
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic 
anticoagulation) 
• 
Patients should not be on therapeutic anticoagulation therapy (prophylactic use of warfarin 1mg 
per day is allowed) and INR should be <1.5 at registration 
• 
The use of anti-platelet agents (e.g. dipyridamole (Persatine), ticlopidine (Ticlid), clopidogrel 
(Plavix)) is allowed only if patient is not receiving aspitin or NSAID's known to inhibit platelet 
function. 
• 
Major surgical procedure (including neck dissection), open biopsy, or significant traumatic injmy 
within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the 
course of the study 
• 
Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, 
within 7 days prior to Day 1 
• 
History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 
• 
Se1ious, non-healing wound, active ulcer, or untreated bone fracture 
• 
Pregnant or breast-feeding women will be excluded. 
 
 
6 
PATIENT REGISTRATION 
Patients must not strut protoco l treatment p1ior to consent being signed and being registrru·. Treatme nt 
shou ld statt within fi ve working days after registration. Subjects can be emolled after eligibility criteria 
are met by calling the site research nurse or designee. 
 
For questions regarding the eligibility of subjects, Anand Kamad, MD, should be contacted at (210) 450- 
1267. 
 
Registration will requit·e the following infmmation: 1) your name, telephone and page number; 2) 
protocol name and number; 3) date treatment begins; 4) subject name; 5) date of bitth; 6) subject hospital 
medical record number; 7) p1ima1ystudy physician; 8) pritna1ytreatment institution; 9) confi1mation of 
eligibility; 10) copies of the info1med consent signature page; 11) verification that the info1med consent 
was signed. 
7 
DOSE MODIFICATIONS - INDUCTION DOCETAXEL / CISPLATIN / CETUXIMAB / 
BEVACIZUMAB (TPE-A) 
All toxicities will be graded according to NCI Common Toxicity Crite1i a AE version 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
Patients who cannot tolerate induction chemotherapy or have delays for more than 3 weeks due to toxicity 
will proceed dit·ectly to chemoradiotherapy even without the completion of 3 cycles of induction. 
Cetuximab or/ and Bevacizumab will NOT be held for known docetaxel and cisplatin toxicities. If 
docetaxel and cisplatin are held to allow for the resolution of known toxicities to these dtugs, cetuximab 
will be allowed to be adtninistered weekly. 
7.1 
Hematologic Toxicity (Docetaxel) 
ANC must be 
1,500/mm3   and  platelet  count must be 
100,000/ LLo n day 1 of each cycle. 
(Reduce doses only for feb1ile neutropenia or if ANC is < 1,000 for > 5 days.) 


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CONFIDENTIAL 
 
 
And 
 
 
Dose modifications on Day 1 based on nadir during previous cycle 
Cisplatin 
Docetaxel 
ANC (per mm3) 
Platelets (per mm3) 
Dose 
Dose 
ANC >= 1000 
>75,000 
100% 
100% 
Or <1000for <5 days 
500-1000 for >= 5 days 
or 
50,000- 75,000 
100% 
80% 
<500 for >= 5 days 
or 
<50,000 
100% 
70% 
 
Febrile neut:ropenia ** 
100% 
70% 
 
**Neutropenic fever is defined as one reading of oral temperanire >38.5°C or tln·ee readings of oral temperanire 
>38.0°C in a 24-hour period. 
 
Dose reductions for reduced ANC are NOT based on a single nadir count. The ANC must remain <1,000 
for :::: 5 days before a dose reduction is made. 
If docetaxel is withheld due to hematologic toxicity, cisplatin should also be withheld, and administered 
when the docetaxel is resumed. No dose reductions of cisplatin will be made for hematologic toxicity. 
In the event that dose adjustments are needed for both ANC and platelets, patients are to receive the lower 
dose. 
Note: prophylactic G-CSF use is recommended. Neutropenic fever is defined as one reading of oral 
temperature > 38.5°C or three readings of oral temperature> 38.0°C in a 24-hour period. 
Treatment should be delayed for up to 2 weeks until the day I ANC is ::::1500 and the plate let count is 
::::1 00 , 000. However 
, if the count s have not recovered in 3 weeks, the patient should start radiotherapy. 
 
Patients and investigators need to be attentive to the possibility of fever and infection so that these 
complications can be promptly and appropriately managed. 
• 
When a dose reduction is made for a decreased ANC, platelet count or febrile neutropenia and the 
reduced dosage results in no toxicity, an attempt should be made to gradually re-escalate the dose 
in subsequent courses. For example, the next course should be given at inte1mediate dose rather 
than full dose, e.g., if a 70% dose results in no toxicity, the next course should sta1t at 80% dose 
rather than 100% (i.e., 70% dose increased to 80% of dose, and 80% dose would be increased to 
100%). 
• 
If chemotherapy must be withheld due to hematologic toxicity, CBC and platelet counts should 
be obtained at least weekly until the counts reach the lower limits for treatment as outlined. The 
treatment schedule will then proceed in the usual sequence. 
• 
No dose reductions will be made for anemia. Patients should be suppo1ted per the treating 
physician's discretion. 


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7.2 
Neurologic Toxicity(Docetaxel, Cisplatin) 
Docetaxel and cisplatin doses should be modified as follows for neurologic toxicity. 
 
Grade of toxicity 
Cisplatin/docetaxel doses to give 
0 
100% 
1 
100% 
2 
Hold treatment until patient recovers to grade O or 1 toxicity , 
then resume treatment at 75% dose. 
3 or worse 
Discontinue treatment 
 
If patients do not recover to grade 0 or I neurotoxicity within 2 weeks, they will be taken off-study. Dose 
modifications made for neurotoxicity are pe1manent reductions. 
7.3 
Ototoxicity (Cisplatin) 
Cisplatin is well known to cause high-frequency heaiing loss. Continued use of the mug does not always 
result in hearing loss, although it may do so. If grade 2 or worse hearing loss is noted, the patient should 
be presented with a discussion of the relative1isks of hea1ing loss versus the potential benefit of 
continuing cisplatin therapy, and a decision made on the continuation of cisplatin. Severe hea1ing loss 
(grades 3 or 4) is an indication to discontinue the mug. 
7.4 
Gastrointestinal Toxicity (Docetaxel, Cisplatin) 
 
7.4.1 
Nausea and/or Vomiting 
Adequate antiemetics for acute and delayed emesis should be given. If grade 3 nausea/vomitingoccurs in 
spite of antiemetics, the cisplatin dose should be reduced by 25% for the next course. Doses of docetaxel 
may be reduced by 25% in subsequentcycles if needed. If tolerated, increase back to I 00% dose as soon 
as possible. 
7.4.2 
Stomatitis 
If stomatitis is present on day I of any cycle , treatment should be withheld until stomatitis has resolved to 
grade 0. 
If Grade 3/4 stomatitis occurs at any time, the dose of docetaxel should be given at 75% dose when the 
mucositis is completely cleared. 
7.5 
Renal Toxicity (Cisplatin) 
Measurement of sernm creatinine is required before each cycle of mug. Modify the Cisplatin dose using 
the following pai·ametesr for calculated creatinine clearance determined in the well-hydrated patient 
using the Cockcroft-Gault formula. The actual weight will be used for the calculation of creatinine 
clearance. 


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CONFIDENTIAL 
 
 
 
 
CrClcma1e)s=  (140-age) x weighl(l<:gy'(creatinine 
x 72) 
CrC  l(females)= CrCl(male)s X 0.85 
 
Creatinine Clearance 
Cisplatin to give 
Docetaxelto give 
60 mL/min 
100% 
100% 
50-60 mL/min 
50% 
100% 
< 50 mL/min 
0% 
0% 
 
If semm creatinine is increased by 100% over baseline or is increased above upper institutional limits, a 
24-hour urine collection with measurement of creatinine clearance is recommended. 
If creatinine clearance is decreased such that treatment is not ad!ninistered as scheduled, repeat the 
abn01mal tests  eve1y week at least. If  the senun creatinine/creatinineclearance returns to baseline (    60 
mL/min), cisplatin may be reinstituted at 50% of the full dose during the next cycle (permanent dose 
reduction). 
If the creatinine clearance is between 50-60 mL/inin, docetaxel should be continued at the dose dictated 
by myelosuppressionand should be given on schedule. If the creatinine clearance is < 50 mL/min, 
withhold any therapy until creatinine clearance improves. Delays in therapy should not be more than 2 
weeks. If a delay of >2 weeks is necessaiy patients should be taken off study. 
If semm creatinine increased at any time to 2-4 mg/dL, a pe1manent dose reduction of cisplatin by 20% 
will be applied; if semm creatinine increased at any time to >4 mg/dL, a pe1manent dose reduction of 
cisplatin by 40% will be applied. 
7.6 
Hepatic Toxicity(Docetaxel) 
The day 1 value should be used in dete1mi ning dose. 
 
Both AST and ALT should be dJ·awn. The more abn01mal of the two values (AST or ALT) should be 
used in dete1mining the dose. 
Patients who develop abno1mal liver function tests for any reason while on the study will have the 
following dose reductions: 
DocetaxelDose Modifications fo1· Abnormal Liver Function 
AST0 1· ALT: 
ALK PHOS: 
ULN 
>1xbut 1.Sx 
>1.Sxbut 
x 
>SxULN 
ULN 
Full Dose 
Full Dose 
Full Dose 
Hold* 
> Ix but 
2.Sx 
Full Dose 
Full Dose 
Reduce Dose by 20% 
Hold* 
>2.Sx but 
Sx 
Full Dose 
Reduce Dose by 20% 
Hold* 
Hold* 
>Sx ULN 
Hold* 
Hold* 
Hold* 
Hold* 


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*Hold until recovered, maximum 14 days, then re-treat at a reduced dose by 20%. "Recovered" is defined as 
meeting the study baseline eligibility criteria. 
 
Bilirubin: Docetaxel should not be administered to patients with senun total bilirnbin >ULN.If serum 
total bilirnbin is >ULN on treatment day, hold docetaxel until sernm total bilirnbin is ::;; ULN (maximum 
14 days), then re-trea t at a reduced dose by 20%. 
7.7 
Hypersensitivity Reactions (Docetaxel) 
See section 8.4 for management guidelines. Discontinueprotocol treatment for Grade 3 or 4 infusion 
related reactions or allergic reactions. There are no dose reductions for infusion related reactions or 
allergic reactions. 
7.8 
Fluid Retention (Docetaxel) 
Fluid retention should be managed as outlined in section 8.5. 
 
7.9 
Other Non-Hematologic Toxicities 
For any grade 3 or 4 toxicity not mentioned above, the treatment should be withheld until the patient 
recovers completely or to grade 1 toxicity then reinstituted (if medically approp1aite). The treatment (both 
cisplatin and docetaxel) should then be resumed at 75% dose(pe1manent dose reduction). 
For grade 1 and 2 toxicities, no dose reduction should be made. 
 
8 
DOSE MODIFICATIONS- RADIATION PLUS CISPLATIN / CETUXIMAB / 
BEVACIZUMAB (XPE-A) 
Prior to initiating chemoradiation, all p1ior toxicities occuned during inductionchemotherapy, except 
alopecia and aneln,ia should have resolved to grade 0-1. 
The following crite1ia should be met to sta1tchemoradiation as per protocol: 
 
• 
Stomatitis should have completely resolved (grade 0) 
• 
ANC 
1500 cells/mm3 
• 
Platelet count of > 100,000 cells/mm
3
 
• 
Creatinine clearance 
60 mL/min 
 
If these parameters are not met, patients may strut radiation therapy alone and receive cisplatin / 
cetuximab / bevacizumab when these c1ite1ia are met. 
If  patients develop significantnon-hematologci  cisplatin-associated toxicities, such as ototoxicity, 
nausea/volniting, and neuropathy (see 8.1.3 below), will receive carboplatin AUC 1.5 weekly instead of 
cisplatin dmi ng chemoradiotherapy.Cisplatin, cetuximab and bevacizumab will only be given 
concunently with radiation. 
Cetuximab or/and bevacizumab will NOT be held for known cisplatin toxicities. If cisplatin is held 
to allow for the resolution of known cisplatin toxicities, cetuximab or/and bevacizumab will be 
allowed to be administered. 


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Dose Modifications for Cisplatin During Chemoradiotherapy 
(For cetuximab and bevacizumab dose modification see above) 
8.1.1 
Neutropenia 
If on the day of scheduled treatment with cisplatin the absolute neutrnphil count {ANC) is < 1000 , hold 
cisplatin until ANC >= l0 00, then treat at 100% dose. Neut:ropenic fever will require pe1manent 25% 
dose reduction. 
8.1.2 
Tlirombocytopenia 
If on the day of scheduled treatment with cisplatin the platelet count is < 75,000, hold treatment until 
platelets are 2:: 75 , 000 , the n treat at 100% dose. Thrombocytopenia that results in bleeding will require 
pe1m anent 25% dose reduction. 
8.1.3 
Neurotoxicity 
If persistent grade 2 neuropathy (>1 week), see 8.1.9 (carboplatin substitution). 
If any signs of grade 3 or greater neurotoxicity occur, discontinue cisplatin. Patients developing grade 3 
or 4 neuropathy will have cisplatin discontinued. 
8.1.4 
Renal Toxicity 
Measurement of senun creatinine is required before each cycle of dtug. Modify  the cisplatin dose using 
the following parameters for calculated creatinine clearance dete1mined in the well-hydt·atedpatient using 
the Cockcroft-Gault fo1mula. 
CrC l(mates) = (140-age) x weight(kgy(sen un creatinine x 72) 
CrCl(females)= ClCr(males) X 0.85 
The actual weight will be used for the calculation of Creatinine Clearance. 
 
Cisplatin should be adtninistered on the scheduled day of treatment using the following guidelines: 
 
Creatinine Clearance 
2:: 60 mL / min 
< 60 ml/min 
C isplat in Dose 
l00% 
0 (Substitute Carboplatin AUC 1.5 weekly) 
 
*If at the time of treatment serum creatinine is increased by 100% or more over baseline or to above 
institutional upper limits of nonnal, a 24-hour mi ne collection with calculation of creatinine clearance is 
recommended. 
If semm creatinine increased at any time to 2-4 mg/dL, a pe1manent dose reduction of 20% will be 
applied; if senun creatinine increased at any time to >4 mg/dL, carboplatin will be used instead of 
cisplatin on all subsequent cycles. 
8.1.5 
Ototoxicity 
Cisplatin is well known to cause high-frequency hearing loss. Continued use of the dtug does not always 
result in hearing loss, although it may do so. If persistent grade 2 heating loss is noted, the patient should 


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be presented with a discussion of the relative risks of hearing loss versus the potential benefit of 
continuing cisplatin therapy, and a decision made on the continuation of cisplatin or switching to 
carboplatin (see 8.1.9). Severe hearing loss (grades 3 or 4) is an indication to discontinue the chu g. 
8.1.6 
Nausea and/or Vomiting 
Adequate antiemetics for acute and delayed emesis should be given. If grade 3 nausea/vomiting occurs in 
spite of antiemetics, the cisplatin dose should be reduced by 25% for the next course. If tolerated, increase 
back to 100% dose as soon as possible. 
8.1.7 
In-field Toxicities During Radiation: Radiation Mucositis I Dysphagia I Dermatitis 
No cisplatin dose adjustments for grade 3 or less radiation mucositis/dysphagia/de1matitis. 
 
Grade 4 radiation mucositis / mucositis / or de1matitis that develops at any time will require pe1manent 
25% dose reduction of cisplatin on all subsequent cycles. If radiation is given in the setting of grade 4 
mucositis / dysphagia / de1matitis, cisplatin will be achninistered with a 25% dose reduction. 
IfRT is held because ofmucositis, hold cisplatin, cetuximab and bevacizumab until RT is resumed. 
8.1.8 
Otller Toxicities 
For any grade 3 or 4 toxicity not mentioned above (except fatigue, anorexia, weight loss, alopecia, 
electrolyte abn01malities that are being cotTected , and any cetuximab-related toxicity), cisplatin should be 
withheld tmtil the patient recovers completely or to grade 1 toxicity after discussing the case with the 
principal investigator. Cisplatin should then be resumed at 75% dose (pe1manent dose reduction). 
For grade 1 and 2 toxicities, no dose reduction should be made. 
8.1.9 
Carboplatin Substitution During Chemoradiotllerapy 
Patient s developing the following cisplatin-induced toxicities will discontinue Cisplatin and substitute 
Carboplatin, AUC 1.5, achninistered as a 30-minute infusion weekly using the following formula to 
calculate the total dose: 
(CrCl + 25) x 1.5 = total mg dose* 
• 
Persistent grade 2 senso1y or motor neuropathy (objective weakness or sens01y loss intetfering 
with function but not interfering with activities of daily living) 
• 
Nephrotoxicity with creatinine clearance < 60 ml/min on the day of schedule chemotherapy 
achninistration , a 1ise in sem m creatinine to >4 mg/dL at any time, or persistent/refract01y 
hypomagnesemia or other electrolyte imbalances and severe kidney abnonnalities that can be 
atttibuted to cisplatin. 
• 
Ototoxicity - Carboplatin may also cause ototoxicity. If hearing loss of grade 1-2 from 
carboplatin is noted, the patient should be presented with a discussion of the relative risks of 
heating loss versus the potential benefit ofreceiving cai·boplatin therap y. Seve re heating loss 
(grades 3 or 4) is an indication to discontinue the carboplatin. 
• 
Grade 4 nausea and vomiting despite approp1iate antiemetics 


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Calculation of Carboplatin Dose: The dose of Carboplatin during chemoradiotherapy will be calculated 
using the following f01mula (Coc kcroft-Ga ult fo1mula): 
Carboplatin Dose(mg)= 1.5 x (CrC I1·2 +25) 
CrClcmates) = (140-age) x weight{kg)/ (serum creatinine x 72) 
CrClcremales=)  CrCl(males)x 0.85 
The actual weight will be used for the calculation of Creatinine Clearance. 
By the end of 2010, all clinical laboratories in the US will use the new standardized Isotope Dilution 
Mass Spectrometly (IDMS) method to measure semm creatinine. The IDMS method appears to 
underestimate serum creatinine values compared to older methods when the semm creatinine values are 
relatively low (e.g., ~0.7 mg/dL). Measurement of serum creatinine by the IDMS-method could result in 
an overestimation of the Glomemlar Filtt·ation Rate (GFR) in some patients with n01mal renal function. If 
the total carboplatin dose is calculated based on IDMS-measured semm creatinine using the Calve1t 
f01mula, carboplatin dosing could be higher than desired and could result in increasedm ug-related 
toxicity. 
The cmrnnt label for carboplatin provides safe dosing instluctions that are based on actual GFR 
measmements. Provided that actual GFR measurements are made to assess renal function, carboplatin can 
be safely dosed according to the insttuctions desc1ibed in the label. 
(http://dailymed.nlm.nih.gov/dailymed/dtu ginfo.cfm ?id= l 3328) 
 
If a patient's GFR is estimated based on semm creatinine measurements by the IDMS method, as 
recollllllended by the FDA, physicians should consider capping the dose of carboplatin for desired 
exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calve1tf01mula described in 
the carboplatin label, the maximum doses can be calculated as: 
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calve1t fo1mula] 
Maximum Carboplatin Dose (mg) = target AUC (mg•min/mL) x (150 mL/min) 
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with n01mal 
renal function. No higher estimated GFR values should be used. 
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg 
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg 
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg 
8.1.10 Carboplatin DoseModifications 
Carboplatin will only be given concmrnntly with radiation. 
• 
Carboplatin will be administered if platelets are 75,000 cells/llllll3 or above and ANC is 1000 
cells/tmn3 or above. Treatlnent will be delayed until the above c1ite1i a are met. 
• 
No carboplatin dose adjustlnents for grade 3 or less mucositis/dysphagia/den natitis. Grade 4 
mucositis/ dysphagia/de1matitis that develops at any time will require a pe1manent dose reduction 


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of carboplatin to an AUC of 1 on all subsequent cycles. If radiation is given in the setting of grade 
4 mucositis/dysphagia/de1matitis, carboplatin will be given at a reduced dose of AUC of 1. 
• 
If in the previous cycle of carboplatin, patients developed grade 4 thrombocytopenia or grade 4 
neutropenia or neutropenic fever, or grade 3 or 4 non-hematologic toxicities with the exception of 
mucositis/dysphagia/ de1matitis, carboplatin dose will be reduced to AUC of 1 in all subsequent 
administrations. 
• 
Ifneuropathy worsens to a grade 3 (impailment of function) after treatment with carboplatin, then 
patients may discontinue chemotherapy for reasons of toxicity at the discretion of the treating 
physician, based on seve1i ty of function loss. 
• 
Patients developing grade 3 or 4 neuropathy will have carboplatin discontinued. 
8.2 
Management of Cetuximab Adverse Reactions and Dose Modifications 
Cetuximab will NOT be held for known docetaxel, cisplatin and bevacizumab toxicities. If 
docetaxel, cisplatin and bevacizumab are held to allow for the resolution of known toxicities to 
these drugs, cetuximab will be allowed to be administered weekly 
Cetuximab will be held or its dose reduced to dose level -1 or -2 (see below) for the following toxicities 
(see 8.2.2 to 8.2.4). 
Cetuximab will NOT be held or reduced for hematologic toxicities. 
Dose levels for cetuxilnab are as follows: 
Cetuximab Dose Levels 
 
 
 
 
Staiting dose 
Weel-dy Cetuxi mab dose 
250 mg/m2 
 
 
Dose Level -1 
200 mg/m2 
Dose Level -2 
150 mg/m2 
 
 
There will be no dose level reductions below a weekly dose of 150 mg/m2. 
8.2.1 
Management of Infusion Reactions 
Severe infusion reactions requil·ethe ilnmediate interruption of cetuximab therapy and pe1manent 
discontinuation from further treatment. Appropriate medical therapy including epinephrine, 
c01ticos teroids, intravenous antihistainines, bronchodilators, and oxygen should be available for use in the 
treatment of such reactions. Patients should be carefully obse1ved until the comp lete resolution of all 
signs and symptoms. 
In clinical trials, lnild to moderate infusion reactions were managed by slowing the infusion rate of 
cetuximab and by continued use of antihistainine pre-medications (eg, diphenhydrainine) in subsequent 
doses. If the patient experiences a lnild or moderate (Grade 1 or 2) infusion reaction, the infusion rate 
should be pe1manently reduced by 50%. For grade 1 or 2 reactions manifesting only as delayed drng 
fever, see below in Section 8.2.2. 


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Cetuximab should be immediately and permanently discontinued in patients who experience severe 
(Grade 3 or 4) infusion reactions. 
8.2.2 
Treatment of IsolatedDrug Fever 
In event of isolated dmg fever, the investigator must use clinical judgment to detennine if the fever is 
related to the study dmg or to an infectious etiology. 
If a patient experiences isolated dmg fever, for the next dose, pre treat with acetaminophen or non- 
steroidal anti-inflammat01y agent (investigator discretion), repeat antipy:retic dose 6 and 12 hours after 
cetuximab infusion. The infusion rate will remain unchanged for future doses. 
If a patient expe1i ences recun:entisolated dmg fever following premedication and post-dosing with an 
approp1i ate antipy:retic, the infusion rate for subsequent dosing should be 505 of previous rate. If fever 
recurs following infusion rate change, the investigator should assess the patient's level of discomfo1t with 
the event and use clinical judgment to dete1ruine if the patient should receive further cetuximab. 
8.2.3 
Management of Pulmonary Toxicity 
In the event of acute onset (grade 2:2) or wo rsening  pu lmona1y symptoms which are not thought to be 
related to underlying cancer, cetuximab therapy should be intenupted and a prompt investigation of these 
symptomsshould occur. If ILD is confirmed, cetuximab should be discontinued and the patient should be 
treated appropriately. 
8.2.4 
Management of DermatologicToxicity 
Patients developing de1m atologic toxicities while receiving cetuximab should be monitored for the 
development of inflammatmy or infectious sequelae, and approp1iate treatment of these symptoms 
initiated. Dose modifications of any future cetuximab infusions should be instituted in case of severe 
(grade 3) acneifonn rash. Treatment with topical and/or oral antibiotics should be considered; topical 
corticosteroids are not recommended. 
If a patient expe1iences severe acneifonn rash, cetuximab treatment adjustments should be made 
according to the following table. In patients with mild and moderate skin toxicity, treatment should 
continue without dose modification. 


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Cetuximab Dose Modification Guidelines 
 
 
Grade 3 
Acneform Rash 
Cetuximab 
Outcome 
Cetuximab 
Dose Modification 
1st occunence 
Delay infusion 
1 to 2 weeks 
Improvement 
Continue at 250 mg/m2 
No Improvement 
Discontinue cetuximab 
2nd occmTence 
Delay infusion 
1 to 2 weeks 
Improvement 
Reduce dose to 200 mg/m2 
No Improvement 
Discontinue cetuximab 
3rd occmTence 
Delay infusion 
1 to 2 weeks 
Improvement 
Reduce dose to 150 mg/m2 
No Improvement 
Discontinue cetuximab 
4th occmTence 
Discontinue 
cetuximab 
Intolerable 
Delay infusion 
Improvement 
Dose reduction by one dose level 
Persistent Grade 2 
1 to 2 weeks 
(only during 
No improvement 
maintenance) 
 
8.2.5 
In-field Toxicities DuringRadiation: Radiation Mucositis I DysphagiaI Dermatitis 
No cetuximab dose adjustments for grade 3 or less radiation mucositis, dysphagia, dennatitis. 
Grade 4 radiation mucositis/dysphagia or de1matitis that develops at any time will require pe1manent dose 
reduction of cetuximab by one dose level on all subsequent cycles. If radiation is given in the setting of 
grade 4 radiation mucositis/dysphagia/de1m atitis, cetuximab will be administered with a dose reduction 
by one dose level. 
IfRT is held becauseof in-field toxicities, hold cisplatni and cetuximab until RT is resumed. 
8.2.6 
Retreatment Criteria/or Cetuximab 
Cetuximab may only be administered if all the following criteria are met regardless of cycle, providing no 
criteria for discontinuation are met: 
• 
Acne-like rash is grade 2 or less 
• 
All grade 3 or 4 non-hematologic out-of-field toxicities (except fatigue, anorex,ia alopecia, and 
dianhea, and any cisplatin/carboplatin or docetaxel-associated toxicities of any grade) have 
resolved to grade 1 or 0. 
• 
Patients with hypomagnesemia and other electrolyte abnormalities can be treated on schedule and 
without a dose reduction if the abno1mality can be con-ected (e.g. intravenous magnesium is given 
for con-ection of hypomagnese mia). 
• 
Cetuximabcan be administered in the setting of any grade hematologic toxicities. 
• 
For in-field toxicities see 8.1.7. 
Discontinue 


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8.3 
Bevacizumab Dose Modification and Toxicity Management 
There are no reductions in the bevacizumab dose. If adverse events occur that require holding 
bevacizumab, the dose will remain the same once treatment resumes. 
Any toxicity associated or possibly associated with bevacizumab treatment should be managed according 
to standard medical practice. Discontinuation of bevacizmnab will have no immediate therapeutic effect. 
Bevacizumab has a terminal half-life of 21 days; therefore, its discontinuation results in slow elimination 
over several months. There is no available antidote for bevacizumab. 
Subjects should be assessed clinically for toxicity prior to, dming, and after each infusion. If 
unmanageable toxicity occurs because ofbevacizmnab at any time during the study, treatment with 
bevacizumab should be discontinued. 
Anaphylaxis Precautions: Anaphylaxis precautions should be observed during bevacizumab 
administration. The patient' s blood pressure and heait rate should be monitored during the infusion. 
Emergency agents including oxygen, oral and endotracheal ailways, intubation equipment, epinephrine, 
antihistatninesand co1t icosteroids should be available. fu the event of a suspected anaphylactic reaction 
dming bevacizumab infusion, stop the bevacizumab infusion and apply a tomniquet proximal to the 
injection site, if possible, to slow systemic absorption of bevacizumab. Administer antihistamines, 
epinephrine, or other medications at the investigatorsdiscretion. 
fufusion Reaction: fufusion of bevacizumab should be intenupted for subjects who develop dyspnea or 
clinically significant hypotension. Subjects who experience a NCI CTCAE v. 4.0 Grade 3 or 4 allergic 
reaction / hypersensitivity, adult respirato1y distress syndrome, or bronchospasm (regai·dless of grade) 
will be discontinued from bevacizumab treatment. 
The infusion should be slowed to 50% or less or intenu pted for subjects who expe1ience any infusion- 
associated symptoms not specified above. When the subject's symptoms have completely resolved, the 
infusion may be continued at no more than 50% of the rate prior to the reaction and increased in 50% 
increments eve1y 30 minutes if well tolerated. fufusions may be restaited at the full rate dmi ng the next 
cycle. 
Adverse events requiling delays or pennanent discontinuation of bevacizumab are listed in the table 
below. 
If bevacizumabis held for any reason, the other study drugs will be given on time assuming 
parameters for their continuation are met and the patient will remain on study. 
Bevacizumab Dose Management Due to Adve1·seEvents 
Eve nt 
Ac tion to be Taken 
Hypertension 
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled to 150/100 mmHg with medication, discontinue bevacizumab. 
Grade 4 
(includinghypertensvi e 
encephalopath)y 
Discontinue bevacizumab 


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Hemorrhage 
No dose modifications for grade 1/2 non-pulmonary and non-CNS events 
Grade 3 
Non-puhnomuyand 
non-CNS hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be discontinuedfrom 
receiving bevacizumab. 
All other subjects will have bevacizumab held until all of the following criteria are 
met: 
The bleeding has resolved and hemoglobin is stable. 
There is no bleeding diathesis that would increase the risk of therapy. 
There is no anatomic or pathologic cond ition that significantlyincreases the risk of 
hemorrhage recmTence. 
Subjects who experience a repeat Grade 3 hemorrhagic event will be discontinued 
from receiving bevacizumab. 
Grade4 non-
puhnonruy or 
non -CNS hemorrhage 
Discontinuebevacizumab 
Grade 1 pulmonary or CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation will be discontinuedfrom 
receiving bevacizumab. 
All oilier subjects will have bevacizumabheld until all of the following criteria are 
met: 
TI1e bleedinghas resolved and hemoglobin is stable. 
There is no bleeding diatl1essi  that would increase the risk of therapy. 
There is no anatomic or pathologic condition that significantlyincreases the risk of 
hemorrhage recmTence. 
Grade 2, 3, or 4 puhnonary or 
CNS hemoll"hage 
Discontinue bevacizumab 
Venou s Tirrombosis 
No dose modifications for grade 1/2 events 
Grade 3 or 4 
Hold study drug treatment. If tlie planned duration of full-dose anticoagulation is < 2 
weeks, bevacizumab should be held until the full-dose anticoagulation period is over. 
Iffue planned duration of full-dose anticoagulation is > 2 weeks, bevacizumab may be 
resmned during tl1e period of full-dose ru1ticoagulation if all of tl1e following c1iteria 
are met: 
The subject must have an in-range INR (usually between 2 and 3) if on warfarin; 
LMWH, warfarin, or other anticoagulant dosing must be stable prior to restarting 
bevacizumab treatment. 
TI1esubject must not have had a Grade 3 or 4 hemorrhagicevent while on 
anticoagulation. 
Alteri.al Tirromboembolic event 
(New onset, worsening, or unstable angin, a  myocru-dial infru·ction, transien t ischemic  attack , cerebro vascular  accident , and 
any oilier arterial thromboembolic event) 
Ally grade 
Discontinue bevacizumab 
BevaciZlllllab Dose Managemen t due to Adverse Events 
Congestive Heart Failure (Left. ventriculru·systolic dysfi.mction) 
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade::; 1 
Grade4 
Discontinuebevacizumab 
Proteintlfia 
Nodose modifications for grade 1/2 events 
[Proteinuria should be monitored by mine analysis for mine protein creatinine (UPC) 
ratio ptior to every other dose of bevacizumab] 


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UPC Ratio 
<3.5 or 24-h mine protein <3.5 
gm 
Continue bevacizumab. 
UPC ratio;::3.5 or 24-h urine 
protein 2:._3 . 5 gm 
Hold bevacizumab until UPC recovers to< 3.5, or 24-h mine protein < 3.5 gm 
Discontinue bevacizumab if urine protein does not recover to < 3.5 after 8 weeks or 
bevacizumab intem.1ption. 
Nephrotic syndrome 
Discontinue bevacizumab 
Fistula 
Any grade (TE fistula) 
Discontinue bevacizumab 
Grade 4 fistula 
Discontinue bevaciZll!nab 
Bowel Obstmction 
Grade 1 
Continue patient on study for partial obstruction NOT requiring medical inte1vention. 
Grade 2 
Hold bevacizumab for partial obstmction requiring medical intervention. Patient may 
restart upon complete resolution. 
Grade 3/4 
Hold bevacizumab for complete obstmction. If surge1y is necessaiy , patient may restait 
bevacizumabaft.er full recovery from surgery, and at investigator' s discretion. 
Wound dehiscence Any grade 
(requiring medical or smgical 
therapy) 
Discontinue bevacizmnab 
Perforation (GI, or at1y other 
organ) 
Discontinue bevacizmnab 
Reversible Poste1i or Leukoencephalopathy 
Any grade 
(confirmed by MRI) 
Discontinue bevaciztunab 
Other Unspecified Bevaci.Zll!nab -Rela ted Adverse Events 
Grade 3 
Grade4 
Hold bevaciztunab until recove1y to :5Grade 1 
Discontinue bevaciztunab 
 
8.4 
Docetaxel-Associated Hypersensitivity Reactions 
Treatment should be discontinued for Grade 3 or 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 
pn ni tus, flushing, rash 
Consider decreasing the rate of infusion until recove1y from 
symptoms, stay at bedside and monitor patient then, complete 
Docetaxel infusion at the initial planned rate 
Moderate symptoms: any symptom 
that is not listed above (mild 
symptoms) or below (severe 
symptoms) such as generalized 
pnni tus, flushing, rash, dyspn,ea 
hypotension with systolic 
• intem1pt Docetaxel infusion 
• give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until 
resolution of symptoms 
• resmne Docetaxel infusion after recove1y of symptoms; 
depending on the physician' s assessment of the patient, 


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BP > 80 lllIIl Hg 
Doceatxel infusion should be resumed at a slower rate, 
then increased incrementally to the initial planned rate, 
(eg. infase at a 8-hour rate for 5 minutes, then at a 4-h 
rate for 5 minutes, then at a 2-h rate for 5 minutes, then 
finally, resume at the Ih infusion rate). 
• 
depending on the intensity of the reaction observed, 
additional oral or N 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 the recommended 1- 
hour infusion, (eg. infuse at a 8-hour rate for 5 minutes, 
then at a 4-h rate for 5 minutes, then at a 2-h rate for 5 
minutes, and finally, administer at thel -h infi,1sion rate ). 
Seve re symptoms: any reaction 
such as bronchospasm, generalized 
urticaria, systolic BP 
80mm Hg, 
angioedema 
• immediately discontinue Docetaxel infusion 
• give diphenhydramine 50 mg N with or without 
dexamethasone 10 mg N 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. 
Grade 3 or 4 infusion related 
reactions or allergic reactions 
DISCONTINUE PROTOCOL TREATMENT* 
In the case of a severe life-threatening anaphylactic reaction, 
docetaxel will not be re-administeredand hence docetaxel will 
be discontinued. 
Following an infusion related reaction or allergic reaction, and 
depending on its severity, additional oral or N premedication 
with an antihistarnine should be given p1ior to the next 
administration and the rate of the infusion should be increased 
gradually to the recommended I-hour infusion rate (e.g. at an 8 
hour rate for 5 rninutes , then a 4 hour rate for 5 minutes, then at 
a 2-hour infusion rate for 5 minutes, then finally, resume at the 
I-hour infusion rate). 
*In case of prolonged or recmTent infusion reactions or allergic 
reactions, following initial improvement, or if hospitalization is 
indicated for clinical sequelae, or if life-threatening 
consequences; urgent intervention is indicated. 
 
8.5 
Fluid Retention Syndrome 
There are no dose reductions for fluid retention. 


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)
 
 
Patients developing new onset edema, progression of existing edema, or another sign of fluid retention 
(eg. 2 pound weight gain) are to be treated with oral diuretics. Regimens found to be effective in the 
management of fluid retention due to Docetaxel are listed below. 
• 
Tliamterene/hydrochlorothiazide one capsule po qd up to tid. 
• 
Furosemide 40 mg po daily if edema progresses despite Triamterene/hydrochlorothiazide therapy. 
Potassium supplementation should be given as needed. 
• 
If after a two-week tlial, furosemide 40 mg po qd is ineffective, the patient may be t1·eated with 
furosemide20 mg po daily plus metolazone 2.5 mg po daily with potassium supplementation as 
needed. 
Fmih er therapy should be customized depending upon the clinical situation. The clinical tolerance of the 
patient, the overall tumor response and the medical judgment of the investigator will detennine if it is in 
the patient' s best interest to continue or discontinue treatment. 
8.6 
Hyperlacrimation 
The excessive lacrimation (epiphora) seen in some patients receiving Docetaxel appears to be related to 
cumulative dose (median 300 mg/m2 and resolves rapidly after treatmentcessation. 
 
Excessive lac1imation seems to be the result of a chemical conjunctivitis and/or chemical inflammation 
(with edema) of the lac1imal duct epithelium (producing a reversible lac1imal duct stenosis). 
Consequently, investigators in clinical trials have treated such patients with (a) artificial tears and/or (b) 
saline eyewash and/or (c) steroid based eye drops. 
It is suggested that the following approach be taken for patients expe1iencing clinically significant 
hyperlaclimation: 
• 
Withhold Docetaxel treatment for 2 weeks, 
• 
Recommend frequent instillation of aitificial teai·s, 
• 
Prescribe a steroid ophthalmic solution (eg. prednisolone acetate) 2 gtts each eye bid for 3 days 
stai·ting the day before Docetaxel administration in patients without a hist01y of herpet ic eye 
disease . 
9 
DURATION OF THERAPY / WITHDRAWAL FROM STUDY 
Patients will receive a maximum of 3 cycles of induction chemotherapy followed by chemoradiotherapy 
as specified in the study design. 
Patients will remain and be followed per protocol even if bevacizumab is discontinued. 
 
Patients who progressed locoregionally post induction may proceed onto chemoradiotherapyas per 
protocol or have salvage surge1yat the discretion of the multidisciplina1yteain. 
 
10 DRUG FORMULATION AND PROCUREMENT 
 
10.1 Docetaxel 
 
10.1.1 Other Names 
Taxotere®, RP56976 


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10.1.2 Classification 
Docetaxel is an antimicrotubule agent that belongs to the taxane family. 
 
10.1.3 Mode of Action 
Docetaxel acts p1i ncipallyby binding to free tubulin and promoting the assembly of tubulin into stable 
microtubules while simultaneously inhibiting their disassembly. As a result, bundles of microtubules 
accumulate and inte1fe re with cell division causing cell cycle anest in M-phase, which ultimatelyleads to 
cell death. In addition, the taxanes have other biological effects, including induction of apoptosis, and 
inhibition of angiogenesis. 
10.1.4 Storage a11d Stability 
Docetaxel vials should be stored between 2 and 25oc(36 and 77° F). Retain in the 01iginal package to 
protect from blight light. Freezing does not adversely affect the product. 
Docetaxel infusion solution, if stored between 2 and 25°C (36 and 77°F) is stable for 4 hours. Fully 
prepared docetaxel infusion solution (in either 0.9% Sodium Chl01ide solution or 5% Dextrose solution) 
should be used within 4 hours (including the 1 hour i.v. administration). 
10.1.5 Dose Specifics 
Docetaxel will be administered at a dose as per 3.1. The BSA will be calculated with the patient's actual 
weight. 
10.1.6 Preparation and Administration 
Docetaxel is a cytotoxic anticancer dmg  and, as with other potentially toxic compounds, caution should 
be exercised when handling and preparing docetaxel solutions. The use of gloves is recommended. Please 
refer to Handling and Disposal section. 
If docetaxel concentrate, initial diluted solution, or final dilution for infusion should come into contact 
with the skin, immediately and thoroughly wash with soap and water. If docetaxel concentrate, initial 
diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and 
thoroughly wash with water. 
Docetaxel for Injection Concentrate requires two dilutions p1ior to administration. Please follow the 
preparation instruct ions provided below. Note: Both the docetaxel for Injection Concentrate and the 
diluent vials contain an ove1ftll. 
10.1.6.1 Preparation of the Initial Diluted Solution 
• 
Gather the appropriate number of vials of docetaxel for Injection Concentrate and diluent (13% 
Ethanol in Water for Injection). If the vials were refrigerated, allow them to stand at room 
temperature for approximately 5 minutes. 
• 
Aseptically withdraw the contents of the approp1iate diluent vial into a syringe and tr·ansfer it to 
the appropriate vial of docetaxel for Injection Concentrate. If the procedure is followed as 
described, an initial diluted solution of 10mg docetaxel/mL will result. 
• 
Mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full 
mixture of the concentr·ate and diluent. Do not shake. 


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CONFDI ENTIAL 
 
 
 
 
• 
The initial diluted docetaxel solution (10 mg docetaxel/mL) should be clear; however, there may 
be some foam on top of the solution due to the polysorbate 80. Allow the solution to stand for a 
few minutes to allow any foam to dissipate. It is not required that all foam dissipates p1ior to 
continuing the preparation process. The initial diluted solution may be used immediatelyor stored 
either in the refrigerator or at room temperature for a maximum of 8 hours. 
10.1.6.2 Preparation of the Final Dilution for Infusion 
• 
Aseptically withdraw the required amount of initial diluted docetaxel solution (10 mg 
docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle of either 
0.9% Sodium Chlo1ide solution or 5% Dextrose solution to produce a final concentration of 0.3 to 
0.74 mg/mL. If a dose greater than 200 mg of docetaxel is required, use a larger volume of the 
infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. 
• 
Thoroughly mix the infusion by manual rotation. 
• 
As with all parenteral products, docetaxel should be inspected visually for paiticulate matter or 
discoloration p1ior to administration whenever the solution and container pennit. If the docetaxel 
for Injection initial diluted solution or final dilution for infusion is not cleai· or appeai·s to have 
precipitation, these should be discai·ded. The final docetaxel dilution for infusion should be 
administered intravenously as a I-hour infusion under ambient room temperature and lighting 
conditions. Contact of the docetaxel concentrate with plasticized PVC equipment or devices used 
to prepai·e solutions for infusion is not recommended. In order to minimize patient exposure to the 
plasticizer DEHP (di-2-ethylliexyl phthalate), which may be leached from PVC infusion bags or 
sets, the final docetaxel dilution for infusion should be stored in bottles (glass, polypropylene) or 
plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined 
administration sets. 
10.1.7 Route of Administration 
Docetaxel will be administered as a 60-minute infusion in saline or D5W through an administration set 
that does not contain phthalate plasticizers along the fluid pathway that is connected to the patient's 
vasculai· access catheter. 
10.1.8 Incompatibilities/Interactions 
Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepai·e solutions 
for infusion should be avoided. Diluted docetaxel solution should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined 
administration sets. 
The metabolism of docetaxel may be modified by the concomitant administration of compounds that 
induce, inhibit, or are metabolized by cytochrome P450 3A4, such as cyclosp01ine, terfenad ine, 
ketoconazole , e1y thromyc in, and troleandomycin. Caution should be exercised with these mugs when 
treating patients receiving docetaxel, as there is a potential for a significant interaction. 
10.1.9 Availability 
Docetaxel (Taxotere®)is commercially available by Aventis. 


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CONFDI ENTIAL 
 
 
 
 
Docetaxel for Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, non- 
aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent (13% ethanol in Water 
for Injection) vial. The following strnngths are available: 
DOCETAXEL 80 MG 
(NOC 0075-8001-80) 
Docetaxel (docetaxel) 80 mg Concentrate for Infusion: 80 mg docetaxel in 2 mL polysorbate 80 and 
diluent for docetaxel 80 mg. 13% (w/w) ethanol in Water for Injection. Both items are in a blister pack in 
one caiton. 
DOCETAXEL 20 MG 
(NOC 0075-8001-20) 
 
Docetaxel (docetaxel) 20 mg Concentrate for Infusion: 20 mg docetaxel in 0.5 mL polysorbate 80 and 
diluent for docetaxel 20 mg. 13% (w/w) ethanol in Water for Injection. Both items are in a blister pack in 
one caiton. 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be 
considered. Several guidelines on this subject have been published. There is no general agreement that all 
of the procedures recommended in the guidelines ai·e necessa1y or approp1iate 
10.1.JO Side Eff ects 
Cardiac: a rrhythmias, pe1icardial effusions (due to fluid retention). Hypotension may occur in 3% of 
patients. Clinically meaningful events such as hea1t fa ilure, sinus tachycai·dia, atti al flu tter, dysrhythmia, 
unstable angina, pulmona1y edema, and hyp e1tension occur rai·ely.8.1% of metastatic  breast cancer 
patients receiving docetaxel 100 mg/m 2 in a rando1nized trial and who had se1ial left ventricular ejection 
fractions assessed developed dete1i oration of LVEF by 2:_l 0%   assoc 
i ated wit h a  drop below the 
institutional lower litnit of n01mal. 
Hematolo gic: d ose -re lated neutropen ia , thro mbocytope n ia , and anetnia. Neutt·openia (< 2000 
neutrophils/1Ilill3) occurs in virtually  all patients given  60-100 mg/m 2 of docetaxel  and  grade 4 
neutt·openia (< 500 cells/1Ilill3) occ urs in 85% of p atien ts given 100 mg/m 2 and 75% of patients given 60 
mg/m2. Febrile neutt·openia occurs in 12% of patients given 100 mg/m2 but is uncolilillon in patients given 
60 mg/m2. The median time to nadir is 7  days, while the  median duration of grade IV neutropenia is  7 
days. Patients with abn01mal ities in liver function tests have an increased 1isk for severe neutropenia, and 
neutt·openic fever, as  well  as severe thrombocytopenia. Neutropenia and thrombocytopenia are 
significantly reduced with weekly schedules of adtninistration. 
Gastrointestinal: nausea and votni ting, diaiThea, and mucosi tis, whic h ai·e generally tnild to moderate. 
Severe gastrointestinal reactions occur in 5% of patients. 
Neurologic: severe neurosens01y symptoms (dysesthesias, pai·esthesias, or pain) occur in up to 6% of 
patients, whereas severe motor neuropathy develops in 4% of patients. 
Hypersensitivity: Severe hypersensitivity reactions chai·acte1i zed by hypotension and/or bronchospasm, or 
generalized rash/e1ythema occurs in 2% of patients premedicated with 3-day c01ticostero ids. Patients with 
a histo1yof life-threatening hypersensitivity reactions should not be rechallenged with docetaxel. 


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CONFIDENTIAL 
 
 
 
 
Fluid retention: Severe fluid retention occurs in 7% of patients despite use of a 3-day dexamethasone 
premedication regimen. It is characterized by one or more of the following events: poorly tolerated 
peripheral edema, generalized edema, pleural effusion requiring mgent drainage, dyspnea at rest, cardiac 
tamponade, or pronounced abdominal distention due to ascites. Fluid retention may be cumulative and is 
less likely to develop with weekly regimens. 
Dermatologic: alopecia, reversible rash, nail changes, and infusion site reactions. Infusion site reactions 
were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, 
phlebitis, extravasation, or swelling of the vein. Severe nail changes with hypo- or hype1pigmentation and 
occasionallyonycholysis and pain may also occur. 
Hepatic: In patients with normal liver function tests at baseline, an elevation in bilimbin occms in 9% of 
cases. Increases in AST or ALT > 1.5 times the ULN, or alkaline phosphatase > 2.5 times ULN, are 
observed in 19% and 7% of patients, respectively. 
Other: asthen ia , dysgeusia , anorex,ia conjunctivitis, epiphora, aithralgia, myalgias. 
 
 
 
Toxicities with 100 mg/m2 of docetaxel 
(patients with normal LFTs) 
Adverse Events 
% 
Neutropenia <2000 cells/mm3 
95.5 
<500 cells/mm3 
75.4 
Thrombocytopenia <100,000 cells/mm3 
8.0 
Anemia <8 g/dL 
8.8 
Febrile Neutropenia 
11.0 
Septic Death 
1.6 
Infections 
(Severe) 
6.1 
Hype1·sensitivity rea ct.ion 
(An y) 
21.0 
(Severe) 
4.2 
With 3-day Premedication 
(Severe) 
2.2 
Fluid retention 
(Any) 
47.0 
(Severe) 
6.9 
With 3-day Premedication 
(Any) 
64.1 
(Severe) 
6.5 
Neurosensory 
(Any) 
49.3 
(Severe) 
4.3 
Cutaneous 
(Any) 
47.6 
(Severe) 
4.8 
Nail changes 
(Any) 
30.6 
(Severe) 
2.5 
Any Gastrointestinal 
(Severe) 
4.7 
Nausea 
38.8 
Vomiting 
22.3 
Diarrhea 
38.7 


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CONFIDENTIAL 
 
 
 
 
St.omatit is 
(Any) 
41. 7 
(Severe) 
5.5 
Alo pecia 
75.8 
Asthenia 
(Any) 
61.8 
(Severe) 
12.8 
Myalgia 
(Any) 
18.9 
(Severe) 
1.5 
Arthralgia 
9.2 
Infusion Site Reactions 
4.4 
(Table modified from Docetaxel PrescribingInforma tion (Aventis). 
PDR 2000.) 
 
 
10.1.11 Nursing Implications 
• 
Monitor CBC with differential and platelet count p1i or to mug adininistration. 
• 
Symptom management of expected nausea, vomiting, and mucositis. 
• 
Advise patients of possible hair loss. 
• 
Patients should be observed closely for hypersensitivity reactions, especially during the first and 
second infusions. 
• 
Resuscitation equipment and medications to treat hypersensitivity reactions should be available 
dming docetaxel administration. 
• 
Monitor liver function tests. 
• 
Evaluate site regularly for signs of infiltration. 
• 
Monitor for symptomsand signs of fluid retention, and pe1ipheral neuropathy. 
 
10.1.12 References 
• 
Docetaxel presc1ibing information (Aventis). PDR 2003. 
• 
BmTsi HA, hvin R, Kuhn J, et al. Phase I clinical trial of Taxotere administered as either a 2-hour 
or 6-hour inti·avenous infusion. JCO 1993;11:950-58. 
• 
Fossella FV, DeVore R, Ken- RN, et al. Randomized phase III ti·ial of docetaxel  versus 
vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously ti·eated 
with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer 
Study Group. J Clin Oncol 2000; 18:2354-62. 
• 
Piccart M.J., Klijn J, Paridaens R, et al. C01ticosteroids significantly delay the onset of docetaxel- 
induced fluid retention: final analysis of a randomized study of the European Organization for 
Research and Treatment of Cancer Investigational Dmg Branch for Breast Cancer. JCO 
1997;15:3149. 
• 
Tomiak, E., Piccait M.J., Kerger, S., et al. Phase I study of docetaxel administered as a I-hour 
inti·avenous infusion on a weekly basis. JCO 1994;12:1458. 
• 
Hainswo1th JD, Bunis HA, Erland JB, Thomas M, Greco FA. Phase I trial of docetaxel 
adininistered by weekly infus ion in patients with advanced refractmy cancer. J Clin Oncol 1998; 
16:2164-8. 
• 
Hainswmth JD, Bm i s HA, Litchy, S. et al. Weekly docetaxel in the treatmentof elderly patients 


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CTRC# 11-36 
October 25, 2016 
 
 
with advanced non-small-cell lung cancer: A Minnie Pearl Cancer Research Network phase II 
trial, Cancer 2000;89:328-33. 
10.1.13 Taxotere Reimbursement Program (PACT+) 
Website: http://www.taxotere.com/hcp/index.asp 
PACT+ offers toll-free support at 1-800-996-ONCO(6626) Monday through Friday, from 8:30 AM to 
6:00 PM Eastern Time, to answer questions about reimbursement, uninsured patients, andm u g 
inf01mation . Messages can be left 24 hours a day. You can also send electronic messages to the PACT+ 
Program at ePACT@access2health.com. 
In addition to calling The Aventis Oncology PACT+ Program, healthcare professionals and patients can 
fax info1mation requests to the PACT+ Program fax number: 1-800-996-6627 
10.2 Cisplatin (Cis-diaminedichloroplatinum, CDDP) 
 
10.2.1 Formulation 
Each vial contains 10 mg or 50 mg of CDDP. Vialsare reconstituted with sterile water. The pH range will 
be 3.5 to 4.5. Cisplatin is also commercially available in solution. 
10.2.2 Storage and Preparation 
Vials of cisplatin are stored at room temperature. When reconstituted as directed, the solution is stable at 
room temperature for 20 hours. When fmther diluted to 0.5 mg/ml with nom1alsaline, it is stable for 72 
hours at room temperature. Cisplatin 10 mg/vial and 50 mg/ml should be reconstituted with 10 and 50 ml 
of sterile water, respectively, resulting in a 1 mg/ml solution. The desired dose of cisplatin is fiuther 
diluted with 250 ml or more of 0.45%-0.9% NaCl and 5% dextrose, or n01mal saline . 
10.2.3 Administration 
Intravenous over 1-2 hours (see treatment plan) 
 
10.2.4 Mechanism of Action 
The mechanism of action of cisplatin has not been clearly elucidated. However, preliminaiy studies have 
indicated that the most likely mechanism of antitumor action of this drug resides in its ability to inhibit 
DNA synthesis and to a lesser degree, RNA and protein synthesis. It has also been shown that DDP binds 
to DNA and produces inter-strand cross-links. Also DDP is not phase-sensitive and its cytotoxicity is 
similar in all phases of the cell cycle. 
10.2.5 Toxicology 
The major effects in humans have been renal toxicity manifested by BUN and sernm creatinine elevation, 
tinnitus and audiologic impailment in the high frequency range (4000 to 8000 Hz), nausea and vomiting, 
hypern1i cemia,mild to moderate anemia, peripheral neuropathy, and electrolyte abno1malities. 
10.2.6 Incompatibilities 
Cisplatin may react with aluminum which is found in some syiin ge needles or IV sets f01ming a black 
precipitate. Cisplatin is less stable in solutions that do not contain chloride ions (e.g. 5% dextrose). 


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10.2.7 Supplier 
C01mnerciallyava ilable. 
 
10.3 Carbopl atin 
 
10.3.1 Other names 
Paraplatin 
10.3.2 Supply and Preparation 
Carboplatin is available in vials containing 50 mg. 150 mg or 450 mg. The content of each vial must be 
reconstituted with either Sterile Water for Injection, D5W, or 0.9% Sodium Chloride. Five mL of the 
diluent should be added to the 50 mg vial, 15 mL to the 150 mg vial and 45 mL to the 450 mg vial for a 
resulting concentration of 10 mg/mL. Carboplatin can be further diluted to concentrations as low as 0.5 
mg/mL with D5W or 0.9% Sodium Chlo1ide. 
10.3.3 Storage and Stability 
Unopened vials of carboplatin are stable for the life indicated on the package when stored at controlled 
room temperature 15°-30°C (59° 86° F), and protected from light. When prepared as directed, carboplatin 
solutions are stable for 8 hours at room temperature (25° C) or for 24 hours refrigerated (2-8° C). 
10.3.4 Mode of Action 
Alkylating agent 
 
10.3.5 Dose and Administration 
Carboplatin will be administered intravenously (see Treatment plan). 
 
10.3.6 Availability 
Commercially available. 
 
10.3. 7 Side Effects 
Hematologic: Bone marrow suppression is the dose-limiting toxicity of carboplatin. (1) 
Thrombocytopenia, with platelet counts below 50,000/mm3, occurs in 25% of the patients (35% of 
pretreated ovarian cancer patients), (2) neutropenia, with granulocyte counts below 1,000/mm3, occurs in 
16% of the patients (21% of pretreated ova1ian cancer patients) and, (3) leuko penia, with WBC counts 
below, 2 000/mm3, occurs in 15% of the patients (26% of pretreated ova1i an cancer patients). The nadir 
usually occurs about day 21 in patients receiving single agent therapy. By day 28, 90% of patients have 
platelet counts above 100,000/mm3; 74% have neutrophil counts above 2,000/mm3; 67% have leukocyte 
counts above 4,000/mm3. Mairnw suppression is usually more severe in patients with impaired kidney 
function. The hematologic effects, although usually reversible, have resulted in infectious or hemorrhagic 
complications in 5% of the patients treated with cai·boplatin. Fever has also been reported in patients with 
neutropenia. Anemia with hemoglobin less than 11 g/dL has been observed in 71% of the patients who 
staited therapy with a baseline above that value. The incidence of anemia increases with increasing 
exposure to carboplatin. Transfusions have been administered to 26% of the patients treated with 
carboplatin (44% of previously treated ovaiian cancer patients). 


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Gastrointestinal: Vomiting occurs in 65% of the patients (81% of previously treated ovarian cancer 
patients) and in about one-third of these patients it is severe. Nausea alone occurs in an additional 10 to 
15% of patients. 
Neurologic: Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% 
of pretreated ovarian cancer patients) with mild paresthesias occun ing most frequently. Carboplatin 
therapy produces significantly fewer and less severe neurologic side effects than  does therapy with cisplatin. 
However, patients older than 65 years and/or previously treated with cisplatin appear to have an increased 
1isk (10%) for peripheral neuropathies. Clinical ototoxicity and other sens01y abn01malities such as 
visual disturbances and change in taste have been rep01ted in only 1% of the patient. Although the overall 
incidence of peripheral neurologic side effects induced by carboplatin is low, prolonged treatme,nt 
particularly in cisplatin-pretreated patients, may result in cumulative neurotoxicity. 
Renal: Development of abno1mal renal function test results is unco1mnon, despite the fact that 
carboplatin, unlike cisplatin, has usually been administered without high-volume fluid hydration and/or 
forced diuresis. The incidences of abn01mal renal function tests reported are 6% for serum creatinine and 
14% for blood urea nitrogen (10% and 22%, respectively, in pretreated ovarian cancer patients). Most of 
these repo1ted abnonnalities have been mild and about one half of them were reversible. 
Hepatic: The in cid ences of abnonnal liver function tests in patients with nonnal baseline values were 
repo1ted as follows: total bilirnbin, 5%; SGOT, 15%; and alkaline phosphatase, 24%; (5%, 19%, and 
37%, respectively, in pretreatedovarian cancer patients). These abn01malities have generally been mild 
and reversible in about one-half of the cases, although the role of metastatic tumor in the liver may 
complicate the assessment in many patients. 
Electrolvtes: The in cidences of abn 01mally decreased serum electrolyte values reported were as follows: 
sodium, 29%; potassium, 20%; calcium, 22%; and magnesium, 29%; (47% 28%, 31%, and 43%, 
respectively, in pretreated ovaiian cancer patients). 
Allergic reactions: Hypersensitivity to carboplatin has been reported in 2% of the patients. These allergic 
reactions have been similar in nature and seve1ity to those rep01ted with other platinum-containing 
compounds, i.e., rash, mticaria, e1ythem, a  prnritus, and rarely bronchospasm and hypotension. These 
reactions have been successfully managed with standard epinephtine, co1ticosteroid, and antihistamine 
therapy. 
Other events: Pain and asthenia were the most frequently repo1ted miscellaneous adverse effects; their 
relationship to the tumor and to anemia was likely. Alopecia was repo1ted (3%). Card iovascular , 
respirat01y, genitouri na1y , and mucosal side effects have occmrnd in 6% or less of the patients. 
10.3.8 Incompatibilities 
Fo1ms a precipitate when in contact with aluminium 
 
10.3.9 Nursing Implications 
Monitor CBC with differential and platelet count p1ior to drng administration. 
Symptom management of expected nausea and vomiting. 


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CONFIDENTIAL 
 
 
 
 
10.4 Cetuximab(C225, ERBITUX) 
Cetuximab is an anti-EGFR human-to-murine chime1ic antibody. Cetuximab is expressed in SP2/0 
myeloma cell line, grown in large scale cell culture bioreactors and pmi fied to a high level purity using 
several pmi fication steps including protein A chromatography, ion exchange chromatography, low pH 
treatment and nanofiltration. Cetuximab is not known to be a vesicant. 
10.4.1 Supplier/How Supplied 
The product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of 
eas ily visible, white, amorphous cetuximab pa1ticulates. Each single-use 50-mL vial contains 100 mg of 
cetuximab at a concentration of2 mg/mL and is f01mulated in a preservative-free solution containing 8.48 
mg/mL sodium chlo1ide, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42 mg/mL sodium 
phosphate monobasic monohydrate, and Water for injection, USP. 
10.4.2 Packaging and Labeling 
Cetuximab for injection will be in single-use, ready-to-use 50-mL vials containing 2 mg/mL of product. 
10.4.3 Handlingand Dispensing of Cetu.ximab 
Cetuximab must be dispensed only from official study sites by authorized personnel according to local 
regulations. Cetuximab should be stored in a secme area according to local regulations. It is the 
responsibility of the Investigator to ensure that study dtug is only dispensed to study patients. 
10.4.4 Storage RequiremenVStability 
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). DO NOT FREEZE. Increased paiticulate 
fo1mation may occur at temperatures at or below 0°C. This product contains no prese1vatives. 
Prepai·aitons of cen1ximab in infusion containers are chemically and physically stable for up to 12 hours at 
2° C to 8°  C (36° F to 46° F) or up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 
77° F). Discai·dany remaining solution in the infusion container after 8 hours at controlled room 
temperature or afier 12 hours at 2° to 8° C. Discai·dany unused po1tion of the vial. 
10.4.5 Preparationand Administration 
Cetuximab must not be adtninistered as an IV push or bolus. 
Cetuximab must be adtninistered with the use of a low protein binding 0.22-micrometerin-line filter. 
Cetuximabis supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a concentration of 
2 mg/mL in phosphate buffered saline. The solution should be clear and colorless and may contain a small 
amount of easily visible white amo1phous cetuximab pa1ticulates. DO NOT SHAKE OR DILUTE. 
Cenlx.imab can be admini stered via infusion pump or syiinge pump. 
 
Infusion Pump: 
• 
Draw up the volume of a vial using a ste1ile syi·inge atta.ched to an appropriate needle (a vented 
spike or other approp1iate transfer device may be used). 
• 
Fill cetuximab into a sterile evacuated container or bag such as glass containers, polyolefin bags 
(eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter Clintec), DEHP plasticized PVC 


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bags (eg, Abbott Lifeca.re), or PVC bags. 
• 
Repeat procedure until the calculated volume has been put in to the container. Use a new needle 
for each vial. 
• 
Administer through a low protein binding 0.22-micrometer in-line filter (placed as proximal to 
the patient as practical). 
• 
Affix the infusion line and prime it with cetuximab before sta1ting the infusion. 
• 
Maximum infusion rate should not exceed 5 mL/min. 
• 
Use 0.9% saline solution to flush line at the end of infusion. 
SVIin ge Pu m p : 
• 
Draw up the volume of a vial using a ste1ile syringe attached to an appropriate needle (a vented 
spike may be used). 
• 
Place the syringe into the syiinge diiver of a syiinge pump and set the rate. 
• 
Administer through a low protein binding 0.22-micrometer in-line filter rated for syringe pump 
use (placed as proximal to the patient as practical). 
• 
Connect up the infusion line and strut the infusion after p1i ming the line with cetuximab. 
• 
Repeat procedure until the calculated vohune has been infused. 
• 
Use a new needle and filter for each vial. 
• 
Maximum infusion rate should not exceed 5 mL/min. 
• 
Use 0.9% saline solution to flush line at the end of infusion. 
• 
Cetuximab should be piggybacked to the patient' s infusion line. 
Following the cetuximab infusion, a I-hour observation pe1iod is recomm ended. 
10.4.6 Availability 
Commerc ially available. 
 
10.4.7 Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves, and Class II ve1tical-lamina.r-air fl ow safety 
cabinets are recommended dming prepai·ation and hand ling . Opened vials must be disposed of at the 
investigational center as chemotherapy or biohazardous waste provideddocumentedproceduresfor 
destmction ai·e in place. 
Cetuximab therapy should be used with caution in patients with known hypersensitivity to Cetuximab, 
mmine proteins, or any component of this product. 
It is recommended that patients weai·sunscreen and hats and limit sun exposure while receiving 
cetuximab as sunlight can exacerbate any skin reactions that may occur. 
10.5 Bevacizumab 
 
10.5.1 Other Names 
RhuMAb VEGF, Avastin 
 
10.5.2 Classification 
Recombinant humanized monoclonal antibody 


CTRC at UTHSCSA 
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10.5.3 Molecular Weight 
Approximate molecular weight is 149,000 daltons 
 
10.5.4 Mode of Action 
Bevacizumab blocks the binding of vascular endothelial growth factor (VEGF) to its receptors resulting in 
inhibition of angiogenesis. 
10.5.5 Description 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody, consisting of93% human 
and 7% murine amino acid sequences. The agent is composed of human IgG framework and mmine 
antigen-binding complementarity-detennining regions. 
10.5.6 How Supplied 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate for 
solution for intravenous (IV) infusion. Bevacizumab may be supplied in 5-cc (I00-mg) and 20-cc (400- 
mg), glass vials containing 4 mL, and 16 mL, respectively (all at 25 mg/mL). Vials contain bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection (SWFI), USP. Vials contain no 
preservative and are suitable for single use only. The monoclonal antibody (bevacizumab) being 
administered is intended for use only in clinical trials. 
10.5.7 Preparation 
Vials contain no preservatives and are intended for single use only. The calculated dose should be placed 
in a sterile, empty IV bag and diluted with a sufficientamount of 0.9% sodium chloride for injection to 
obtain a final volume of I00 mL. 
10.5.8 Storage 
Upon receipt of the study dmg, vials are to be refrigerated at 2°C-8°C (36°F-46°F) and should remain 
refrigerated until just ptior to use. DO NOT FREEZE. DO NOT SHAKE. Vials should be protected from 
light. 
Opened vials must be used within 8 hours. VIALS ARE FOR SINGLE USE ONLY. Vials used for I 
subject may not be used for any other subject. Once study drng has been added to a bag of ste1ile saline, 
the solution must be administered within 8 hours. 
10.5.9 Stability 
Shelf-life studies ofrhuMAb VEGF are ongoing. The ste1ile single use vials contain no antibacte1ial 
preservatives. Therefore, vials should be discarded 8 hours after initial entty. 
Once diluted in 0.9% sodium chloride, solutions of bevacizumab must be administered within 8 hours. 
 
10.5.10 Route of Administration 
Intravenous 
All conventional chemotherapy dtugs, including Bevacizumab, are adtninistered according to institutional 
practices. It is the practice of the Cancer Therapy and Research Center (CTRC) and University Hospital 
(UH) to give Bevacizumab in 30 minutes beginning with the first dose. Safety data published in the 


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CONFDI ENTIAL 
 
 
-
 
 
Journal of Clinical Oncology and elsewhere have shown that bevacizmnab is safe with few 
hypersensitivity reactions and thus has been adopted as cmrnnt policy at CTRC and UH80 81. The 
investigators recognize this policy is different from the FDA label for bevacizmnab. All patients are 
monitored for potential reactions. Vital signs at CTRC are recorded on study specific flowsheets pre- and 
post-bevacizumab infusion. Vital signs at UH are recorded pre-bevacizumab infusion and then eve1y 4 
hours while patient is in the clinic for treatment. See Section 3.1.1 Treatment and Premedications. To 
insure complete delive1y of bevacizmnab, the IV infusion line must be flushed with 0.9% sodium 
chloride. The following are two recommended methods for flushing the bevacizmnab IV infusion line: 
• 
When the bevacizmnab infusion is complete, add an additional 50mL of 0.9% sodium chl01ide  
for injection to the bevacizumab infusion bag. Continue the infusion until a volume equal to that 
of the volume contained in the tubing has been administered. 
• 
Replace the empty bevacizmnab infusion bag with a 50mL bag of 0.9% sodium chloride for 
injection and infuse a volume equal to the volume contained in the tubing. 
NOTE: The flush is not included in the total recommended infusion times. 
 
10.5.11 Availability 
The bevacizmnab will be supplied by Genentech. 
 
10.5.12 Patient Care Implications 
Measurement of blood pressure and dipstick mi nalysis should be pe1fo1med p1ior to each dose of 
bevacizumab. Hypertension will be monitored through routine evaluation of blood pressure prior to each 
bevacizumab treatment. Optimal control of blood pressure according to standard public health guidelines 
is recommended for patients on treatment with or without bevacizumab. Discontinuation of therapy 
should be considered if the patient expe1iences uncontrolled hype1tension. 
Proteinmi a will be monitored by mine protein: creatinine (UPC) ratio or dipstick at least eve1y 6 weeks . 
Monitor patient closely dming infusion, for infusion related events and for bleeding. 
Instrnct patient to monitor and repo1tsigns of bleeding, increased cough, swelling. 
 
Treat pain, aithralgias, etc. with acetaminophen, or other pain relief strategies that do not inte1fere with 
the clotting cascade. 
10.5.13 Side Effects 
Allergy/Immunology: Allergic reaction/hypersensitivity. Infusion-related reactions. 
Blood/Bone Marrow: Leukopenia, neutropenia, thrombocytopenia. 
 
Cardiac: Hype1t ension/hypertensive c1isis, cai·diac ischelnia/ infarction, supraventriculai·an hythlnia, left 
ventriculai·dysfunction (congestive heait failure), hypotension, syncope. 
Constitutional symptoms: Asthe nia, fever, 1i gors/chills, weight loss. 
Dermatologylslan: Exfoliative de1m atitis, complications with wound healing, rash, skin ulceration, 
urticai·ia 


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Gastrointestinal: GI perforation and wound dehiscence, sometimes complicated by intra-abdominal 
abscesses. Lru·ge bowel leakage, GI fistula, intestinal obstruction, intestinal necrosis, mesenteric venous 
occlusion, colitis, mucositis/stomatitis, nausea, vomiting, anorexia, constipation, diruThea, 
hea1tbum /dyspepsia , dty mouth , taste disturbance. 
Hemorrhage/Bleeding: Life -threatenin g or  fatal puhnona1y hemotThage (primarily in lung cancer 
patients), CNS bleeding, GI hemotThage, subarachnoid hemo tThage , hemotThagic stroke, epistaxis (nose 
bleeds), vaginal bleeding, gum bleeding. 
In fection : Infection with normal ANC. 
 
Metabolic/Laboratorv: Increased: alkaline phosphatase, ALT (SGPT), AST (SOOT), Bilirnbin, senun 
creatinine.Hyponatremia and hypokalemia. 
Neurology: Cerebrovasculru·ischemia, dizziness, abnonnal gait, confusion. 
 
Ocular: Excessive lacrimation. 
Pain: Abdominal pain, chest/thoracic pain, headache, ruthralgias, myalgias, generalized. 
Pulmonarv/Upper Respiratorv: Dyspnea , cough, bronchospasm/wheezing, voice changes (hoarseness). 
 
Renal/Genitourinarv: P ro tein mi, a   nephrotic syndt·ome. 
 
Reversible Posterior Luekoen-cephalopathy Syndrome: Possible blindness , stro ke sy mpt oms, stro ke . 
 
Vascular: Life-threatening and potentially fatal a1te1ial thromboembolic events: cerebral infarction, 
transient ischemic attacks, myocardial infru·ction and angina. Venous thromboembolic events: deep vein 
thrombosis, intra-abdominal thrombosis. 
11 CLINICAL AND LABORATORY EVALUATIONS 
 
11.1 Evaluations at Screening / Baseline 
(Perfo1med within 4 weeks of registration unless othe1wise indicated) 
• 
Histmy and physical examination, including vital signs, weight and perfo1mance status 
dete1mination (within 1 week ofr egistration). 
• 
Complete blood counts, including platelets and INR (within I week of registration). 
• 
Blood chemistty studies, including creatinine, electrolytes (K+, Na+ , CJ-, C O 2), calc ium , Mg 
(within 1 week of registration) and liver function tes,ts  including bilirnbin, AST (SGOT, ) 
(SGPT), and alkaline phosphatase (within I week ofr egistt·ation). 
ALT 
• 
If urine dipstick result is > 1+, a calculation of Utine Protein Creatinine (UPC) ratio is required. 
Patients must have a UPC ratio < 1.0 to pruticipate in the study. 
• 
Pregnancy test (when applicable, within 3 days prior to treatment initiation) 
• 
PET/CT scans and CT of the chest and other imaging studies as indicated for staging and baseline 
tumor measurements. Any scans or x-rays used to document measurable disease should be done  
as close to study entty as possible and within 4 weeks p1ior to registt·ation. 
• 
Dental evaluation (within 6 weeks of registration) 
• 
ENT evaluation/endoscopy (within 6 weeks ofr egistration) 


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• 
Swallowing assessment (within 6 weeks ofregistration) 
• 
Audiometly (within 6 weeks of registi·ation) 
• 
Quality of life questionnaire (complete FACTHN questionnaire in Appendix F) 
• 
Blood samples for research purposes 
• 
Obtain archival tumor sample of unstained slides 
• 
Tumor biopsies at baseline (optional) for con elative studies 
• 
EKG (All patients will have a baseline EKG. If abnonnaliti es consistent with active coromuy 
a1tery disease are detected, the patient will be refe1rnd to a card iologist for approp1iate evaluation 
and management p1ior to treatlnent on study.) 
11.2 Evaluation During Treatment 
 
11.2.1 Induction - Prior to Each Treatment Cycle, Day 1 
• 
Histo1y and physical examination, including vital signs, weight and perfo1mance status 
dete1mination 
• 
Hype1tension will be monitored through routine evaluation of blood pressure prior to each 
bevacizumab treatlnent. Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without bevacizumab. 
• 
Toxicity assessment 
• 
Complete blood counts, including platelets 
• 
Blood chemistty studies, including creatinine, electrolytes (K +, Na+, er-, CO 2), c a++, Mg++, and 
liver function tests, including bilirnbin, AST (SGOT), ALT (SGPT), and alkaline phosphatase 
• 
Urine for protein: creatinine ratio (and 24 hour collection if indicated). Proteinuria should be 
monitored by mine dipstick prior to eve1y other dose of bevacizumab. If urine dipstick is > I+ 
then UPC ratio should be dete1mined. 
• 
Blood samples for con elatives studies (p1ior to cycle 2) 
• 
Tumor biopsies on cycle I, day 21 (plus/minus 2 days) (optional) for correlative studies 
11.2.2 Induction- after cycle 3 
• 
Evaluations as after cycle I and 2 (see above) 
• 
ENT evaluation/endoscopy 
• 
PET/CT scan 
• 
CT scan of chest 
• 
Response assessment by clinical and by radiographic evaluation (repo1ted separate ly) in prima1y 
and lymph nodes 
• 
QOL questionnaire 
• 
Swallowing assessment 
• 
Blood samples for con elativesstudies (p1ior to staiting radiation therapy) 
• 
Urine for protein: creatinine ratio (and 24 hour collection if indicated). Proteinuria should be 
monitored by mine dipstick prior to eve1y other dose of bevacizumab. If urine dipstick is > I+ 
then UPC ratio should be dete1mined. 
11.2.3 Cllemoradiotherapy - weekly and 2 weeks after completion 
• 
Hist01y and physical examination. A focused evaluation of toxicities on a weekly basis will be 


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performed at a minimum. A complete histmy and physical examination is needed at least eve1y 3 
weeks. 
• 
Hype1tension will be monitored through routine evaluation of blood pressure prior to each 
bevacizumab treatment. Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without bevacizumab. 
• 
CBC, platelets and creatinine/electrolyteswill be pe1fo1med at the time of cisplatin administration 
at a lninimum. 
• 
Vitals signs will be checked eve1y time cetuximab is administered. 
 
• 
Urine for protein: creatinine ratio (and 24 hour collection if indicated). Proteinuria should be 
monitored by urine dipstick prior to eve1y other dose of bevacizumab. If urine dipstick is > 1+ 
then UPC ratio should be dete1mined. 
11.2.4 Evaluation After Completion of Radiation (8 weeks after) 
• 
Histmy and physical examination 
• 
Complete blood counts, including platelets 
• 
Blood chemistly studies, including creatinine, electrolytes (K+, Na+ , er-, C O 2), c a++, Mg++ , and 
liver function tests, including bilirnbin, AST (SGOT), ALT (SGPT), and alkaline phosphatase 
• 
ENT evaluation/endoscopy 
• 
PET/CT scan 
• 
CT scan of chest 
• 
Response assessment by clinical and by radiographic evaluation (repo1ted separate ly) in prima1y 
and lymph nodes 
• 
Blood samples for co1Telati ves s tudi es 
• 
Urine for protein: creatinine ratio (and 24 hour collection if indicated). If urine dipstick is > 1+ 
then UPC ratio should be dete1mined. 
11.3 Evaluations at Follow Up 
Staiting 8 weeks after completion of radiation, patients will be followed eve1y 3 months for 2 yeai·s and 
then eve1y 6 months for 3 years, and subsequently annually for a total of 10 yeai·s. (Follow up evaluation 
will include assessment of late toxicities, such as dysphagia, G-tube feedings requirements, xerostomia, 
and others.) 
Quality of life assessments will be repeated at 3 months and 12 months after radiation completion. 
Tumor assessments will be perfo1med 8 weeks after completion of radiotherapy. Subsequently, repeat 
imaging with CT scan of neck/chest will be perfo1med eve1y 3 months x 2 times, and then eve1y 6 months 
for the first 3 years. Subsequent scans eve1y 6 months until the 5th year and then annually ai·e 
recommended but not required. 
Swallowing assessments will be perfonned as standard practice at baseline and 3 months post 
chemoradiotherapy and then as indicated. 
Blood samples will be collected for co1Telat ive s 6 m ont h s after completion of radiation. 


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CONFIDENTIAL 
7? 
 
 
 
STUDY PARAMETERS TABLE 
Baseline 
Prior to Each 
Treatment 
Cycle, Day 1 
After 3 Cycles of 
induction 
During CRT 
Weekly and 2 
weeks post RT 
8 weeks after 
CRT 
Off therapy 
Follow-Up 
History and physical exam 
X 
X 
X 
x• 
X 
X 
Height 
X 
Weight 
X 
X 
X 
x• 
X 
Vital signs 
X 
X 
X 
x• 
T oxicity assessment 
X 
X 
X 
X 
X 
Perfonnance Status 
X 
X 
X 
x• 
X 
CB,C Differential, Platelets1 
X 
X 
X 
x• 
X8 
Creat inine, Electrolytes (K'", Na • , er-, CO,,) Mg • +,c a++ 
X 
X 
X 
x• 
X8 
Liver enzymes ' 
X 
X 
X 
X 
Chest X-ray (optional) 
X 
Urine for protein (every2 bevacizumab infusions) 11 
X 
X 
X 
X 
Pregnancy test' 
X 
PET/CTscan 
X 
X 
X 
CT scan of the neck/chest 
(can be part of PET/CT) 
X 
X 
X 
x• 
Bonescan,if clinically indicated 
X 
Tumor measurements• 
X 
X 
X 
x• 
Swallowing assessment ' 
X 
X 
X 
Dental evaluation 
X 
QOL assessment (FACT-HN)' 
X 
X 
X 
Audiometry 
X 
Pathology materials6 
X 
Blood samples 7 
X 
X 
X 
X 
X 
ENT evaluation/endoscopy 
X 
X 
X 


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Baseline 
Prior to Each 
Treatment 
Cycle, Day 1 
After 3 Cycles of 
induction 
During CRT 
Weekly and 2 
weeks post RT 
8 weeks after 
CRT 
Off therapy 
Follow-Up 
EK<f 
X 
Tumor biopsies (optional)'" 
X 
X 
All patients should be seen by a Medical Oncologist, an ENT surgeon, and a Radiation Oncologist prior to initiating therapy. Unresectabilityshould be determined by a multidisciplinaryteam. 
NOTE: For H+P required on every cycle day 1, patients can be seen the previousday (due to long duration of druginfusions on cycle day 1). 
1 
Complete blood counts with differential and platelet count should be performed< 24 hours prior to chemotherapy administration(withthe exception of baseline CBC). ln the event of grade 3 or 4 hematologic 
toxicity, follow-up CBC ,vithdifferential and platelet count willbe obtained every 1-3 daysuntil there is evidence of hematologic recovery. During CRT, CBC will be performed on the day of cisplatin 
administration at a minimum. 
2 
Liver fimction tests should include: Bilirubin, AST (SOOT), ALT (SGPT), and alkaline phosphatase shouldbe performed <24 hours prior to chemotherapy administration 
3 
All females of childbearing potential musthavea negative pregnancy test done within 3 days of initiation of treatment to rule out pregnancy 
4 
Tumor measurements will be made usingphysical examination, including endoscopic examination (clinically) and PET/CT scans (radiographically). Clinical and radiographic assessments will be reported 
separately. Response in the primary and the neck will be reported separately as well. Tumor assessments willbeperformed after 3 cycles of induction and 8 weeks after completion of chemoradiotherapy using 
PET/CT. Subsequently, no specific tumor measurements are required. Patients willbe categorized as having progression of disease or not. A repeat imaging with CT scan of neck/chest willbeperformed    every 
3 months for 2 years, and then every 6 months for 3 years. Subsequent scans every 6 months until the 5th year and then armually are recommended but not required. 
5 
QOL assessments (FACT-H&N, version 4) will be performed at baseline, after completion of induction therapy, at 3 months, and 12 months post chemoradiotherapy. Swallowing assessments willbe 
performed at baselin, e  3 months follow up, and if problems pers,ist  at 12, 24, 3,6  48, and 60 months follow up. 
6 
The following materials willbe submitted (optional studies): paraffin-embedded tumor specimens for i.nnnunohistochemistryand molecular studies. 
7 
Blood samples for DNA/RNA and EGFR studies will be obtained a) at baseline, b) prior to cycle 2, c) after 3 cycles of induction, d) 8 weeks aftercompletion of chemoradiotherapy (see section 13.0 for 
details). Samples will be forwarded as specified in the correlative study section (13). 
8 
During chemoradiotherapy and in the i.nnnediate 2 week period following RT completion, patients needa focused evaluation of toxicities on a weekly basis. However, a complete history and physical 
examination is onlyneeded every3 weeks. CBC and electrolytes/creatini.ne willbeperformed at the timeof cisplatin administration at a minimum and willalso be repeated 2 weeks post completion of 
radiation. Vitals signs willbechecked everytimecetuximab is administered. 
9 
EKG (All patients will have a baseline EKG. 1f abnormalities consistent with active coronary artery diseaseare detected, the patient willbereferred to a cardiologist for appropriate evaluation and 
management prior to treatment on study.) 
10 
Tumor biopsies at baseline (optional) and on cycle 1, day 21 (plus/minus 2 days)(optional) 
11 
UPC ra tio is requi red for patients with dipstick > 1+. 
CRT=chemoradiotherapy 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
 
 
 
12 SUBJECT DISCONTINUATION 
Subjects who cannot receive one of the drugs will still remain on study and be followed per protocol unless they withdraw 
consent. C1iteria for removal from study are: 
• 
Disease progression 
• 
Study closure 
• 
Unacceptable adverse event(s) as defined in dose modification or other unacceptable AEs 
• 
Patient decision to withdraw from the study, or 
• 
In the judgment of the investigator, fmt her treatment would not be in the best interest of the patient. 
 
 
The following will require discontinuationof bevacizumab: 
• 
If the patient develops anaphylaxis to bevacizumab 
• 
Grade 4 hype1t ension or Grade 3 hype1tension not controlled with medication 
• 
Nephrotic syndrome 
• 
Grade 
2 pulmonary or CNS hemoIThage ; any Grade 4 hemorrhage 
• 
Symptomatic Grade 4 venous thromboembolic event requiring full dose warfrui n or eq uiva lent (i .e ., 
unfract ionated or low molec u lar we ight hepru"in) 
• 
Any grade rut erial thromboembo lic event 
• 
Grade 4 congestive herut failure 
• 
Gastrointestinal perforation 
• 
Tracheoesophageal fistula (any grade) or Grade 4 fistula 
• 
Grade 1 bowel obstrnction that has not fully recovered despite medical or surgical intervention 
• 
Wound dehiscence requiti ng medical or surgical intervention 
• 
Unwillingness or inability of subject to comply with study requil·ements 
• 
Determination by the investigator that it is no longer safe for the subjectto continue therapy 
• 
All Grade 4 events thought to be related to bevacizumab by the investigator 
 
Patients who have an ongoing bevacizumab-related Grade 4 or se1iou s ad ve 1·se event at the time of discontinuation 
from study treatment will continue to be followed until resolution of the event or until the event is considered 
irreversible. 
NOTE: Patients will remain and be followed per protocol even if bevacizumabis discontinued. 
 
13 STATISTICAL METHODS 
 
13.1 Sample Size 
The Simon's optimal two- stage design will be used to test whether the administration of induction with cisplatin, 
docetaxel, cetuximab and bevacizumab followed by cisplatin, cetuximab, bevacizumab and radiation yields a complete 
response rate that is of clinical interest. The histo1ical control is our previousstudy (UPCI 05-003) in which the complete 
response (CR) rate after TPE was 21% (by PET). We assume that the CR rate with TPE plus Avastin will be significantly 
higher. This design will test the null hypothesis that the trne CR rate is less than or equal to 21% versus the alternative 
hypothesis that it exceeds 40%. The sample size of 30 response-evaluable patients (Subjects that complete the induction 
phase of the study and at least have staited the concmTent chemo-radiation pa1t before discontinuing therapy) will provide 
81% power to reject the null hypothesis when the hue response rate is 40%, with the type I e1rn r rate at 7.6%. The 
CONFIDENIATL  
74 


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regimen will be considered of clinical interest if there are 10 or more complete responders out of the total of 30 response- 
evaluable patients. 
The following Simon's optimal two-stage design uses 30 patients to test the null hypothesis that the tme CR rate is at most 
21% versus the alternative hypothesis that it exceeds 40%. 
Stage 1: Enrollment will be placed on hold after the first 3 patients strut the study treatment. They will be 
evaluated for any unexpected toxicities until completion of study treatment. A repott will be subtnitted to the 
DSMC and IRB prior to continuing study accrnal. Toxicities will also be assessed in the first 13 patients. If 1 
grade 5 or unexpected toxicities occur compared to UPCI 05-003, the study will be reviewed by the DSMC. The 
trial regimen will also be assessed after the first 13 evaluable patients. If 2 or fewer patients have a complete 
response (CR), the ttial will be tenninated for insufficient efficacy and the accrnal of patients will be stopped. If 3 
or more patients have a CR, then accrnal will continue in the second stage oft his tt·ial. 
Stage 2: Enter an additional 17 evaluable patients to the tti al. Thus, a total of 30 patients will be studied. If the 
total number responding is less than or equal to 9 in the total 30 evaluable patients, the tt·ial tt·eatment will be not 
concluded effective. If 10 or more CRs are observed in the total 30 evaluable patients, then this treattnent will be 
considered protnising in this patient population and will be evaluated futt her in future studies. 
A minimum of 2 cycles of induction is required for response assessment. Response-Evaluable patients ru·e s tu dy - 
el i gible patien ts (i.e. , t hose meeting all of the protocol inclusion/exclusion c1ite1i a) who complete a tninimum of2 cycles 
of induction. Determination of evaluability will be done by the laborato1y and the study principal investigator. It can be 
assumed that some patients will not be evaluable for response. Thus, more than 30 patients may need to be enrolled to 
obtain 30 response-evaluable patients. Assutning a 10% inevaluability rate, a total of about 33 patients will be enrolled. 
13.2 Analyses 
The CR rate will be estimated by the numberof CR dividedby the total number of evaluable patients. Confidence 
intervals for the ttue CR rate will also be calculated. 
Smvival data will be analyzed using Kaplan-Meier analysis. The median, 2-ye,ar 3-year, 5-yeru·overa ll smvival and the 
c01Tespond ing 95% confidence inte1val will also be repmted. 
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to 
determine toxicity patterns. Point estimation and Confidence Interval estimation will be done for toxicities. 
Statistical analyses will also be done for the following: 1) local/regional and distant failme rates, point estimation and 
Confidence Inte1val estimation; 2) acute and late QOL changes associated with tt·eattnent with induction 
docetaxel/cetuximab/cisplatin followed by cisplatin plus cetuximab given concmTen tly with standard radiotherapy. 
Longitudinal QOL analysis will be pe1fom1  ed to compru·e FACT -HN  scores before and after therapy. The first site of 
recurrence will be recorded and used as the reference point for the calculation of the time to locoregional or distant 
progression. 
13.3 Definition of response 
Response c1iteria will as previously used by Passero et al (Annals of Oncology 2010;21:2278-83).79 CR by PET is defined 
as complete disapperu·ance of FDG activity attiibutable to malignancy, without regard to the degree of CT response, 
assessed on combined PET-C T. Patients without CR on PET (non-CR) will be categorized as having either abnonnal 


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CONFIDENTIAL 
 
 
 
 
findings but unlikely to be malignant or abnormal findings likely to represent residual malignancy with recommendations 
to undergo tissue sampling as clinically appropriate. 
Patients will have PET-CT at baseline, after induction and after completion of RT. Beyond this third PET-CT scan no 
specific Tumor Measurements are required. We will categorize to either progression or no progression. 
14 CORRELATIVE STUDIES 
 
14.1 Background and Methods 
We plan to collect tissue and blood samples for potential future studies. A panel of candidate biomarkers including 
markers of proliferation, apoptosis and activation of EGFR and VEGF signaling pathways as well as HPV will be 
evaluated. Analysis ofbiomarkers will be explorato1y. 
14.2 Material Submission 
 
14.2.1 Tissue Biomarker Studies 
 
14.2.1.1 Sample Submission Schedule 
Paraffin-embedded specimens will be used. 
These studies will be perfo1med at baseline , p1ior to treatment initiation and after first cycle, day 21 (± 2 days as an 
optional tumor biopsy for patient who provide info1med consent for it). Specimens that have been already collected for 
diagnosis will be generally used. 
14.2.1.2 Sample Preparation Guidelines 
A representative paraffin block of the 01iginal diagnosis and all repeat biopsies, if available, will be subtnitted. If blocks 
cannot be submitted, 10 unstained slides of 4 micron section mounted on positively-charged glass slides are acceptable. 
If you have any questions regarding sample collection, processing, and shipping contact: 
Jennifer S. Carew, PhD or Steffan T. Nawrocki, Ph.D. 
Co-Director, Preclinical Research 
CTRC Institute for Drng Development 
Assistant Professor 
Depa1t ment of Medicine/Division of Hematology and Medical Oncology 
University of Texas Health Science Center at San Antonio 
7979 Wurzbach Road, MC 8232 
RoomG437 
San Antonio, TX 78229 
Phone: 210-450-3894 
Email: Nawrocki@uthscsa.edu 
Email: Carew@uthscsa.edu 
14.2.1.3 Shipping Procedures 
Specimens will be shippedovernight. DO NOT SHIP ON FRIDAY OR BEFORE A HOLIDAY. Ship to Dr. Carew or 
Dr. Nawrocki at the above address. 
14.2.1.4 Methods 


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Methods will include but not limited to immunohistochemishy, FISH, and detection of HPV16 using in-situ hybridization. 
Immunohistochemistiy for the determination of biomarkers will be perfo1med using commercial antibodies. Prin::taiy 
antibody incubation, secondaiy antibody detection complex using Dako Envision plus, followed by DAB. Heat induced 
antigen rehieval will be applied. Tissue microairnys will be constiu cted, if feasible. 
14.2.2 BloodBiomarker Studies 
Blood samples (about 5mL each) will be collected for co1Telatives at the following tin::te point s (p1ior to treatment that day 
unless othe1wise indicated): a) baseline prior to cycle 1, day 1, b) prior to cycle 2, c) cycle 3, p1i or radiation, d) 8 weeks 
after completion of radiation, e) 6 months after completion of radiation. 
14.3 Banking 
The residuals and/or derivatives of samples collected and submitted for studies associated with this protocol will be 
retained by the Principal Investigator for possible use in future studies. If future use is denied or withdrawn by the patient, 
the samples will be removed from consideration for use in any future study. 
14.4 Blood Correlatives for Lavender Top and Serum Red Top Tubes 
Blood samples (34 cc) will be collected at each tin::te po int as li ste d above. 
 
Sample Collection Methods 
• 
Before venipuncture, the phlebotomist prepares two ?ml lavender top tubes and two red top plastic 5 ml blood 
collection tube (red top #1 and #2) and affixes a label to each blood collection tube. Info1mation to be encoded 
on the label includes the clinical tI"ial study n umber, subject's unique identification (ID) number and date. The 
tubes ai·e placed in a test tube rack, in order of collection (lavendertops, then red tops). 
• 
The phelobotomist uses standard venipuncturetechniques. Approxin::tate blood volume to be collecte d in each 
tube is as follows: 7 mL in each lavendertube and 5 ml in each red top tube. 
• 
The phlebotomist affixes the Subject ID on to the blood collection f01m. 
• 
The phlebotomist uses the blood collection fo1m to record duration of fast before phlebotom, y  date and time of 
phlebotomy, approximate amount of blood collected into each tube, complications from phlebotomy, and staff 
initials. 
 
14.5 Methods 
 
Instructions for blood processing protocols for lavender top tubes #1, #2 and red top tube #1 and #2 are 
outlined below. CTRC Pharmacokintetic laboratory personnel will can y out these procedures. 
LavenderTop Tubes (PBMC) 
 
• 
Samplesshouldbe processed as soon as possible after receipt. 
• 
Allowblood to equilibrateto room temperatur.e 
• 
Centrifuge lavender top tubes #1 and #2. 
• 
Transfer separated plasmaand aliquotinto 1 ml volumesin1.8ml cryovials labeledwith specimennumbe,rcontents of tube 
(plasma), volumeand date. 
• 
Freeze plasma at -80° C. 
• 
Replace plasmawith an equal volumeof PBS and mix bloodby inversion. 


CT RC at UT HSCSA 
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CONFIDENIATL 
 
 
 
 
• 
Aliquotbloodmixtureinto 15 ml tubes containing1.5 ml per each tube. 
• 
Add 7.5 ml ELbufef r (Qiagen#79217,)vortex,and place on icefor 10 minutes. 
• 
After 10 minutes, the bloodshould be transparent. If not, replace on ice for an addition10 minutes. 
• 
Centrifugetubes containing bloodat 1,300x g for 10 minutesat room  temperatrue. 
• 
Aspirateand discardthesupernatant. 
• 
Resuspendthe pellet in 3mls of EL buffer, placein 3 ml cryovial, and centrifugefor 10 minutesat 1,300 x g at room 
temperatuer. 
• 
Carefully aspirate supernatant. 
• 
Add 0.6 ml RNA Later(Qiagen #76106) to the pellet andlabelthe tube with the specimen number, "1.5 ml bloodPBMC", and 
date. 
• 
Store samplesat -80°C. 
• 
RNA,DNA and protein will be subseqeuntlyisolated using Al PrepDNA/RNA/Protein mini kit (Qiagen #80004). 
• 
De live r to Steffan Nawrocki (Nawrocki@uthscsa.edu) or Claudia Espitia Olaya (Espitia@uthscsa.edu). 
 
 
Red Top Tubes (Serum) 
• 
To allow clot fmmation, red top tubes sit at room temperature (22° to 25° C) for at least 30 to 45 minutes. 
• 
If futther processing cannot be accomplished immediately after clot retraction, red top tubes should be placed at 
40 C. 
• 
Centr ifuge r ed t op tu bes. If futt her processing can not be accomplished within 5 minutes after completing 
centrifugatio n, red top tubes should be placed at 4° C. 
• 
Inspect and record if serum shows signs of hemolysis, ictems, and/or turbidityTransfer serum into labeled freezer 
tubes. Aliquot 1ml of sera per 1.8 ml c1yovial. 
• 
Info1mation to be encoded on each tube includes the specimen number con esponding to the sample collection, the 
contents of the freezer tube (sernm), volume and date. 
• 
Freeze and store at -80° C until shipment to Dr. Nawrocki or Dr. Carew. 
 
Anticipated aliquot distribution 
 
Collection tube 
Contents of fre.ezer tube 
 
Number of aliquots per 
tube 
 
 
Lavender  #1 & #2 
PBMC 
Red top #1 & #2 
Serum 
4-5 
Total 
11 
 
 
14.6 SWpping 
The ce ll pellet from the CPT collection tubes and the sernm c1yovials are to be delivered to: 
Jennifer S. Carew, PhD, 
Steffan T. Nawrocki, Ph.D. (or Claudia Espitia Olaya) 
Co-Director, Preclinical Research 


CT RC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
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CONFIDENTIAL 
 
 
 
 
CTRC Institute for Dmg Development 
Assistant Professor 
Department of Medicine/Division of Hematology and Medical Oncology 
University of Texas Health Science Center at San Antonio 
7979 Wurzbach Road, MC 8232 
Room G437 
San Antonio, TX 78229 
Phone: 210-450-3894 
Email: Nawrocki@uthscsa.edu 
Email: Carew@uthscsa.edu 
Email: espitia@uthscsa.edu 
 
Please send e-mail notification to the above laborat01y contacts to ensure someone is there to receive samples. Include 
patient's initials, date and cycle drawn and time sample drawn. 
15 DATA SAFETY MONITORING 
Data and Safety Monitoring Oversight 
 
A Data and Safety Monit01ing Plan is required for all an individual protocols conducted at CTRC. All protocols 
conducted at CTRC are covered under the auspices of the CTRC Institutional Data Safety Monit01ing Plan (DSMP). 
 
The CTRC Institutional DSMP global policies provide individual ttials with: 
 
• 
Institutional policies and procedures for institutional data safety and monitoring, 
• 
An institutional guide to follow, 
• 
Monitoring of protocol accmal by the CTRC Protocol Review Committee, 
• 
Review of study forms and orders by the Fonns Committee, 
• 
Independent monitoring and source data ve1ification by the CTRC QA Monitor/Auditor 
• 
Tools for monitoring safety events, 
• 
Monitoring of UPIRSO's by the Director of Quality Assurance and DSMC, 
• 
Deten nining level of 1isk (Prio1ity of Audit Level Score - PALS), 
• 
Oversight by the Data Safety Monit01ing Committee (DSMC), and 
• 
Ve1ification of protocol adherence via annual audit for all Investigator Initiated Studies by the CTRC Quality 
Assurance Division. 
 
 
Monitoring Safety 
 
Due to the risks associated with participation in this protocol, the CTRC Data Safety Monitoring Board (DSMB) #2 in 
conjunction with the Plincipal Investigator will pelf01m assessment of adverse events, adverse event trends and tt·eatment 
effects on this study. The CTRC DSMB #2 acts as an independent DSMB for Investigator Initiated Studies (ITS) 
cond u cted at CTRC. The CTRC DSMB #2 will monitor data throughout the duration of a study to dete1mine if 
continuation of the study is approp1iate scie ntifically and ethically. The CTRC DSMC who will review the DSMB's 
qua1terly rep01ts provides an additional layer of review. 
 
Baseline events and adverse events will be captured using the CTRC Master Adverse Events Document for each patient 
using CTCAE V4.0 for the grading and atttibution of adverse events. Usage of the CTRC Master Adverse Events 
Docl.lIIlent centt·ally docl.lIIlents: 
 
• 
Th e event and grades the seriousness of the event, 


CT RC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
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CONFIDENTIAL 
 
 
 
 
• 
If the event was a change from baseline, 
• 
The detennination of the relationship between the event and study intervention, 
• 
If the event was pait of the nom1al disease process, and 
• 
What actions were taken as a result of the event? 
 
 
 
Reporting Requirements 
 
For this stud, y  the Master Adverse Events Documents collected on patients for this protocol will be reviewed by the 
Principal Investigator on a monthly basis to determine if a serious safety problem has emerged that result in a change or 
eai·ly tennination of a protocol such as: 
 
• 
Dose modification, 
• 
Suspending enrollment due to safety or efficacy, or 
• 
Termination of the study due to a significant change in risks or benefits. 
 
The PI will provide the DSMB #2 with the monthly findings for discussion and review dming their meetings. 
 
As per the CTRC DSMP, any protocol modifications, problematic safety repo1ts, unanticipated problelllS, and suspension 
or eai·ly tennination of a tiial must be rep01ted to the DSMB #2 and all members of the reseai·ch team . Suspension and 
early termination of a ti·ial must also be rep01ted immediately to the Director of Quality Assmance who will promptly 
notify the sponsor and the UTHSCSA IRB. 
 
The PI will review the Master Adverse Events documents to detemline the significance of the reported events and will 
provide findings to the DSMB #2 after the third patient completes ti·eatment for which toxicity analyses will also be 
performed, after an additional 10 patients are accmed and completed ti·eatment, eve1y 6 months , at the end of study, and 
as necessaiy should significant adverse events ai·ise. The DSMB #2 will review the infonnation provided by the PI and 
repo1t to the CTRC DSMC on a bi-annual basis unless an emergent issue has been identified. The Investigator Initiated 
Study DSMC Repo1t F01m includes infonnation on adverse events, cunent dose levels, number of patients enrolled, 
significant toxicities per the protocol, patient status (morbidity and mortality), dose adjustments with observed response, 
and any intelim findings. Any trend consisting of three or more of the same event will be repo1ted to the CTRC DSMC 
for independent review outside of the bi-annual reporting cycle, which begins three months following protocol sta1t up. 
DSMB #2 will also provide its findings to the CTRC's Regulato1yAffairs Division so that it may be provided to the 
UTHSCSA IRB with the protocol's annual progress repo1t. Conflict of interest is avoided by the independent reviews of 
the CTRC DSMB #2, CTRC DSMC and by ongoing independent review ofUPIRSO's by the Director of Quality 
Assmance. 
 
All SAE and UPRISO' s will be rep01ted following CTRC and UTHSCSA institutional guidelines. 
 
UTHSCSA SAE/UPRISO REPORTING REQUIREMENTS 
Type Event 
Report to 
Timeframe 
All AE, SAE and UPIRSO 
Regulato1y Affairs and DQA 
Same as other notification timeframes 
except for SAE/AE which should be 
reported on Monday for tl1e prior week 
SAE 
Clinical Trial Sponsor 
Within 24 hours 


CT RC at UTHSCSA 
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CONFIDENTIAL 
 
 
 
 
AE/SAE 
UTHSCSA IRB 
Annually 
UPIRSO - all 
Clinical Trial Sponsor 
Within 24 hours of the PI determining a 
UPIRSO exists 
UPIRSO - life threatening 
UTHSCSAIRB 
Within 48 hours of the PI determining a 
UPIRSO exists 
UPIRSO - non-life threatening 
UTHSCSAIRB 
Within 7 days of the PI determininga 
UPIRSO exists 
 
 
Expedited Reporting for Phase II and III Studies (including hospitalization.:. 
 
U NEXPECTED EVENT 
EXPECTED EVENT 
GRADES2 - 3 
Attribution of 
Possible, Probable 
or Definite 
GRADES4 - 5 Regardless of 
Attribution 
GRADES 1 - 3 
GRADES 4 - 5 Regardless of 
Attribution 
Expedited report 
within 10 working 
days 
Rep011 by phone to IDB 
within 24 hrs. Expedited 
rep011to follow within 10 
working days. 
Adverse Event 
Expedited 
Expedited repo11, including Grade 5 
Aplasia in leukemia patients, within 10 
working days. 
Grade 1 - Adverse 
Event Expedited 
Reporting NOT 
required.) 
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 rep011ed 
within 10 working days. 
Reporting NOT 
required. 
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 
rep011ed within 10 working days. 
Grade 4 Myelosuppression or other Grade 
4 events that do not require expedited 
rep011ing will be spec ified in the protocol. 
 
* For Hospitalization Only - Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated hospitalization (or 
prolongation of existing hospitalization) must be repmted regardless of requirements for Phase of study, expected or 
unexpected and attribution. 
 
Expedited repo1t ing may not be appropriate for specific expected adverse events for ce1tain later Phase II and Phase III 
protocols. In those situations the adverse events that will not have expedited repo1ting must be specified in the text of the 
approved protocol. An expected Grade 3 event that is definitely related to the investigational agent is only to be repo1ted if 
the patient is hospitalized using the generic repo1ting criteria. For instance, in a trial of an investigational agent where 
Grade 3 dianhea requiring hospitalization is expected, only dian hea requiring ICU care (Grade 4) might be designated for 
expedited repo1ting. 
 
Setious adverse events on NCI sponsored trials utilizing a commercially available agent (with no IND's involved)will 
additionally be rep01ted via the FDA's Medwatch program. 


CTRC at UTHSCSA 
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CONFIDENIATL 
 
 
 
 
AssU1ing Com pli ance with Protocol and Data Accuracy 
As with all studies conducted at CTRC, the PI has ultimate responsibility for ensuring protocol compliance and data 
accuracy/integrity. Protocol compliance, data accuracy and repo1ting of events is finther ensured by an annual audit 
conducted by the Data Safety Officer, whose audit report is shared with the PI, the research team and will be reviewed by 
the CTRC DSMC. 
 
 
CTRC DSMB Membership 
 
The CTRC has two DSMB's with a prima1yset of members specific to the histology of the study consisting ofUTHSCSA 
faculty and staff. This Protocol will utilize DSMB#2. 
 
DSMB #2 (for Solid Tumors) 
C. Richard Meier, MD 
Melissa Nashawati, MPA 
YuanYuan Liang 
 
As per NCI guidelines and to eliminate conflict of interest (financial, intellectual, professional, or regulato1y in nature), 
the CTRC DSMB specific to this study will not treat patients on this protocol. Usage of the DSMB specific to the 
histology has been created to ensure that expe1ts in that histology are represented on the DSMB assembled for this 
protocol, but may be expanded, at the PI's discretion, to include other members which may include: 
 
• 
Expe1ts in the fields of medicine and science that are applicable to the study (if not CU1Tently represented on the 
DSMB), 
• 
Statistical expe1t s, 
• 
Lay representatives, 
• 
Multidisciplina1y representation, from relevant specialties including expe1ts such as bioethicists , biostat istic ians 
and basic scientists, and 
• 
Others who can offer an unbiased assessment of the study progi·es. 
 
Additional or alternate membership of in the DSMB is selected by the DSMC chair, in conjunction with the PI of this 
protocol. 
 
CTRC DSMB Chaiter and Responsibilities 
 
The CTRC DSMB will provide inf01mation on the membership composition, including qualifications and expe1ience to 
both the UTHSCSA IRB and CTRC PRC for review. The CTRC DSMB for this study will act as an independent 
adviso1y board to the PI and will repo1t its finding s and recommendationsto the PI, the UTHSCSA IRB and the CTRC 
DSMC. CTRC DSMB repo1ts will utilize the Investigator Initiated Study DSMC Rep01t F01m and meetings will occur 
on a monthly basis to review any updates from the p1ior mee ting. 
 
Once the protocol is activated, if not afready established elsewhere in the protocol the CTRC DSMB will establish and 
provide: 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
 
 
 
• 
Procedures for maintaining confidentiality; 
• 
Statistical procedures including monitoring guidelines, which will be used to monitor the identified prim.my, 
seconda1y, and safety outcome valiables; 
• 
Consider factors external to the study when relevant infonnation becomes available, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics of the study; 
• 
Plans for changing frequency of interim analysis as well as procedures for recommending protocol changes; 
• 
Recommendation of dose escalation, MTD recommendation of eat"ly terminat ion based on efficacy results; 
• 
Recommendation of tennination due to unfavorable benefit-to-risk or inability to answer study questions; 
• 
Recommendation of continuation of ongoing studies; 
• 
Recommend modification of sample sizes based on ongoing assessment of event rates; and 
• 
Review of final results and publications. 
 
 
16 RETENTION OF RECORDS 
• 
In addition to the regulat· hospital chatt, a sepat·ate patient folder will be kept which includes: 
o 
The patient's signed, dated and witnessed consent 
o 
Pathologic documentation of squamous cell cat·cinoma of the head and neck 
o 
The Completed Patient Registration Fo1m and all other study fo1ms 
o 
Completed Patient Registration Fo1m . Eligibility c1i te1ia will be cleat·ly stated. 
o 
Baseline info1mation will include: age, gender, race, feeding tube placement, smoking and alcohol 
hist01y, pe1f01mance sta tus, TNM staging, sites of disease involvement, and quality of life assessments. 
o 
Flow Sheet (see Appendix)reflectingpretreatment test results and the first therapy. 
o 
Measurement Fonn showing baseline measurement (measurable disease patients). 
o 
Pathology Repo1t (pathologic confum ation of disease.) 
o 
Signed, date, d  and witnessed Patient Info1mation and Consent Fo1m. 
o 
Evaluat ion f01ms after induction therapy (3 cycles) and after completion of chemoradiotherapy. Clinical 
and radiographic response will be repo1t ed. Also, response in the prima1yand lymph nodes will be 
reported sepat·ately.Measurement Fo1ms: after each lesion measurement or evaluation, whichever is less 
frequent. Measurement fo1m s must give se1ial measurements or evaluatio ns as required by protocol to 
assess disease response to therapy. Follow-up fo1m s will repo1t the presence of feeding tube and late 
toxicities. 
o 
A final Treatment Summaty Form is to be sublnittedwhen the patient progresses, dies, or goes off study 
for any other reason. Any subsequent head and neck surge1y will be rep01ted. 
o 
Follow-Up Fo1m is sublnitted at the time the patient goes off study at any time p1i or to treatment 
completion as scheduled and thereafter, eve1y 3 months for the first 2 years, then eve1y 6 months for the 
next 3 yem·,sand subseq uently ann ually for a total of 10 years. 
o 
Death must be rep01ted, using the Follow-Up F01m 
 
 
 
 
 
 
 
 
 
CONFIDENIATL 
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CTRC at UTHSCSA 
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Januaiy 14. 2015 
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CONFIDENIATL 
 
 
 
 
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Januaiy 14. 2015 
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CONFIDENIATL 
 
 
 
 
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48. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidennal growth factor receptor 
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refract01y metastatic and/or recmTent squ amous cell carcinoma of the head and neck. J Clin Oncol 
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49. Pfister DG, Su YB, Kraus DH, et al. ConcmTent cetuximab, cisplatin, and concomitant boost radiotherapy for 
locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality 
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51. Taylor SGt. Why has so much chemotherapy done so little in head and neck cancer? J Clin Oncol 1987; 5:1-3. 
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53. Rosenthal DI, Pistenmaa DA, Glatstein E. A review of neoadjuvant chemotherapy for head and neck cancer: 
pa1tia1ly shm nken tumors may be both leaner and meaner. Int J Radiat Oncol Biol Phys 1994; 28:315-20. 
 
54. Taylor SGt, Mmthy AK, Vannetzel JM, Colin P, Dray M, Caldarelli DD, et al. Randomized compa1ison of 
neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced 
head and neck cancer. J Clin Oncol 1994; 12:385-95. 
 
55. De Andres L, Bnmet, J Lopez-Pousa A, Burgues, J Vega M, Tabemero JM, et al. Randomized tiial of 
neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-MO head and 
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56. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, T1iozzi P, et al. Randomized comparison of 
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Januaiy 14. 2015 
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CONFIDENIATL 
 
 
 
 
carcinoma of the head and neck: a Southwest Oncology Group study. Journal of Clinical Oncology 1992; 
10:1245-51. 
 
57. Vokes EE, Stenson K, Rosen FR, Kies MS, Rademaker AW, Witt ME, et al. Weekly Carboplatin and Paclitaxel 
followed by concomitant Paclitaxel, Fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ- 
preserving therapy for advanced head and neck cancer. J Clin Oncol 2003; 21:320-6. 
 
58. Machtay M, Rosenthal DI, Hershock D, Jones H, Williamson S, Greenberg MJ, et al Organ preservation therapy 
using induction plus concmTent che moradiation for advanced resectable oropharyngeal carcinoma: a University of 
Pennsylvania Phase II Trial J Clin Oncol 2002; 20:3964-71. 
 
59. Gaspar C, Pesudo C, An ibas L, Climent MA, Mengual JL, Molinas C, et al. Induction chemotherapy (ICT) 
followed by concomitant chemoradiotherapy (CT/RT) for advanced squamous cell carcinomas of head and neck 
(SCCHN). Ann Oncol 2002; 13 (Suppl. 5):152. 
60. Weaver A, Fleming S, Ensley J, Kish JA, Jacobs J, Kinzie J, et al. Superior clinical response and survival rates 
with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally 
advanced head and neck cancer. American Journal of Surge1y 1984; 148:525-9. 
61. Di Blasio B, Barbie1iW, Bozzetti A. A prospective randomized trial in resectable head and neck carcinoma: loco- 
regional treatment with and without neoadjuvant chemotherapy. Proc Am Soc Clin Oncol 1994; 13:279(abstract). 
 
62. Shin DM, Glisson BS, Khmi FR, Lippman SM, Ginsberg L, Diaz E, Jr., et al. Phase II study of induction 
chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell 
carcinoma of the head and neck. Cancer 2002; 95:322-30. 
63. Axel Grothey, Elie E. Hedrick, Robe1t D. Mass, Somnath Sarkar, Sam Suzuki, Ramesh K. Ramanathan, Herbe1t 
I. Hmwitz, Richard M. Goldberg, Daniel J. Sargent. Response-Independent Survival Benefit in Metastatic 
Colorectal Cancer: A Comparative Analysis ofN9741 and AVF2l 07. Journal of Clinical Oncology, Vol 26, No 2 
(Janua1y 10), 2008 : pp. 183-189 
64. Giantonio BJ, Catalano PJ, Meropol NJ, OD wyer PJ, Mitchell EP, Albe1ts SR, Schwa1tz MA, Benson AB 3rd; 
Eastern Cooperative Oncology Group Study E3200. BevaciZUlllab in comb inat ion w ith ox aliplatin, fluorouracil, 
and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern 
Cooperative Oncology Group Study E3200. J Clin Oncol. 2007 Apr 20;25(12):1539-44. 
 
65. Sandler AB, GrayR , Peny MC, et al. Paclitaxelcarboplatin alone or with bevaciZUlllab for non -small cell lung 
cancer. NEngl JMed 2006;355:2542A50 . 
 
66 . Miller KD. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin 
Breast Cancer. 2003 Feb;3(6):421-2. 
 
67. Ozcan C, Wong SJ, Ha1i P. Reversible poste1i or leukoencephalopathy syndro me and bevacizumab. N Engl J Med. 
2006 Mar 2;354(9):980-2; discussion 980-2. 
68. Glusker P, Recht L, Lane B. Reversible poste1i or leukoencephalopathy syndrome and bevacizumab. N Engl J 
Med. 2006 Mar 2;354(9):980-2; discussion 980-2. 


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69. Scappaticci FA, Fehrenbacher L, Cartwright T, Hainswo1th JD, Heim W, Berlin J, Kabbinavar F, Novotny W, 
Sarkar S, Hmwitz H. Surgical wound healing complications in metastatic colorectal cancer patients treated with 
bevacizumab. J Surg Oncol. 2005 Sep 1;91(3):173-80. 
70. Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C, Qian D, Monis L, TidwellM, Chen H, Zwiebel J. Targeting 
vascular endothelial growth factor for relapsed and refracto1y adult acute myelogenous leukemias : therapy with 
sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004 Jun 
1;10(11):3577-85. 
71. Wedam SB, Low JA, Yang SX, Chow CK, Choyke P, Danfo1th D, Hewitt SM, Be1man A, Steinberg SM, 
Liewehr DJ, Plehn J, Doshi A, ThomassonD, McCaithy N, Koeppen H, She1man M, Zujewski J, CamphausenK, 
Chen H, Swain SM. Antiangiogenic and antitmnor effects of bevacizumab in patients with inflammato1yand 
locally advanced breast cancer. J Clin Oncol. 2006 Feb 10;24(5):769-77. Epub 2006 Jan 3. 
72. D'AdamoDR, Anderson SE, Albritton K, Yamada J, Riedel E, Scheu K, Schwaitz GK, Chen H, Maki RG. Phase 
II study of doxornbicin and bevacizumab for patients with metastatic soft-tissue sarcomas. J Clin Oncol. 2005 Oct 
1;23(28):7135-42. 
73. Posner M R, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova Vet al; Cisplatin and 
Fluorouracil Alone or with Docetaxel in Head and Neck Cancer. NEJM Volume 357:1705-1715, 2007. 
 
74. Veimorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and 
neck cancer. N Engl J Med. 2007;357:1695-1704. 
 
75. Lindel K, Beer KT, Laissue J, Greiner R.H, Aebersold D.M. Human papillomavirns positive squamous cell 
carcinoma of the oropha1ynx. A radiosensitive subgroup of head and neck carcinoma. Cancer 2001;92:805-13. 
 
76. Mork J, Lie A K, Glattre E,Clark S,Phil D, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller J.T, 
Wang Z, Youngman L, Lehtinen M, DillnerJ. Human Papillomavirns Infection as a Risk Factor for Squamous- 
Cell Cai·cni oma of the Head and Neck. NEJM 2001 (15) 344:1125-1131 
77. Licitra L, Pe1rnne F, Bossi P, Suai·diS, Mai·iani L, Altusi R, Oggionni M, Rossini C, Cann) G, Squadrelli M, 
Quattrone P, Locati L.D, Bergamini C, Olmi P, Pierotti M.A, Pilotti S. High-Risk Human PapillomavirusAffects 
Prognosis in Patients With Surgically Treated Orophaiyngeal Squamous Cell Carcinoma.JCO 2006, Vol 24, No 
36: 5630-5636. 
78.Hui E.P, Ma B.B, Leung S.F, King A D, Mo F, Kam M.K, Yu B.K, Chiu S.K, Kwan W.H, Ho R, Chan I,  Ahuja  A 
T, Zee B.C, Chan A T. Randomized Phase II Trial of ConcmTent Cis platin-Radio therapy Wi th or Without 
Neoadj uvant Docetaxel and Cisplatin in Advanced Nasopha1yngeal Carcinoma. J Clin Oncol. 2009 Jan 
10;27(2):242-9. 
79.V. A Passero, B. F. Bra11Stetter , Y. S hu ai , D . E . H eron , M . K . Gi b son , S . Y. L a i , S . W . Kim, R. L. Fenis, J. T. 
Johnson, A Argiris.  "Response  assessment  by  combined positron  emission  tomography  and  CT  scan  versus 
RECIST in patients with locally advanced head and neck cancer treated with  chemoradiotherapy"  Annals of 
Oncology 2010;21:2278-83 
 
80. L. H. Dohn, B. V. Jensen, F.0 Lai·sen. "Sho1ttime infusion of bevacizumabin combination with 5FU-based 
chemotherapy as first-line therapy in a non-selective patient group with metastatic colorectal cancer." Acta Oncol, 
2010; 49: 395-396. 


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81. D. L. Reidy, K. Y. Chung, J. P. Timoney, V. J. Park, E. Hollywood, N. T Sklarin, R. J. Muller, L.B. Saltz. 
"Bevacizmnab 5mg/kg can be infused safely over 10 minutes." JCO 2007; 25 (19): 2691-2695. 


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APPENDIX A: ECOG PERFORMANCE STATUS 
 
 
 
Grade 
ECOG 
0 
Fully active, able to canyon allpre-diseasepe1fo1mance without restiiction 
1 
Restiicted in physically strenuous activity but ambulat01y and ab le to cany out work of a light or 
sedentaiy nature, e.g., light house work, office work 
2 
Ambulato1y and capable of all selfcare but unable to cany out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot cany on anyselfcare.Totally confined to bed or chair 
5 
Dead 


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APPENDIX B: PROCEDURE FOR OBTAINING A URINE PROTEIN / CREATININE RATIO 
 
 
1) Obtain at least 4 mL of a random urine sample (does not have to be a 24 hour urine) 
2) Determine protein concentration (mg/dL) 
3) Determine creatinine concentration (mg/dL) 
4) Divide #2 by #3 above: urine protein / creatinine ratio = protein concentration (mg /dL) / creatinine concentration 
(mg /dL) 
The UPC directly con elates with the amount of protein excreted in the urine per 24 hrs (i.e. a UPC of 1 should be 
equivalent to 1 g protein in a 24 hr urine collection) 
Protein and creatinine concentrations should be available on standard reports of urinalyses, not dipsticks. If protein and 
creatinine concentrations are not routinely repo1ted at an Institution, their measurements and repo1t s may need to be 
requested. 


CT RC at UT HSCSA 
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CONFIDENIATL 
 
 
 
 
 
 
 
APPENDIX C: NCI COMMON TOXICITY CRITERIA (CTCAE V 4.0) 
 
 
See: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


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APPENDIX D: FDA MEDWATCH 3500A FORM 
 
 
See: www.fda.gov/medwatch/safety/FDA-3500A fillable.pdf 


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APPENDIX E: NEW YORK HEART ASSOCIATION (NYHA) GUIDELINES 
 
NYHA Classification 
Excerpted from Oxford Textbook of Medicine. Vol 2, p.2228. Oxford Press.1997. 
 
Class 
Description 
I 
Subjects with cardiac disease but without resulting limitations 
of physical activity. Ordinruy physical activity does not cause 
undue fatigue, palpitation, dyspnea, or angina}pain. 
II 
Subjects with cru·diac disease resulting in slight limitation of 
physical activity. They ru·e comfortable at rest. Ordinruy 
physical activity results in fatigue, palpitation, dyspnea, or 
angina} pain. 
III 
Subjects with cru·diac disease resulting in mru·ked limitation of 
physical activity. They are comfortable at rest. Less than 
ordina1y physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
IV 
Subjects with cru·diac di seas e re sult ing in inability to canyon 
physical activity without discomf01t. Symptoms of cardiac 
insufficiency or of the angina}syndrome may be present event 
at rest. If any physical activity is unde1taken, discomfo1t is 
increased. 


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APPENDIX F: FACT - H&N 
 
 
Quality of Life, Pe1fo1mance and Patient Prio1ities 
 
 
1) Patient Name:   
 
 
 
2P)atient ID #:  /_  / _/   -/_  /_  /_  / 
 
 
3) Date: /_ 
/_ /_ /_ 
/_ /_ / 
 
 
4) Assessment Point: 
/ 
/ 
1 = baseline 
2 = post induction 
3 = 3 months follow-up 
4 = 12 months follow-up 
 
 
FACT - H&N (Version 4) 
 
Below is a list of statements that other people with your illness have said are imp01t ant. By circling one number per line, 
please indicate how true each statement has been for you during the past 7 days. 
 
  
PHYSICALWELL-BEING 
 
GPl I have a lack of energy 
GP2 I have nausea 
 
GP3 Because of my physical condition, I have trouble 
meeting the needs of my family 
 
GP4 I have pain 
 
 
GP5 I am bothered by side effects of treatment 
not at 
all 
a little 
bit 
some- 
what 
quite 
a bit 
very 
much 
0 
1 
2 
3 
4 
0 
1 
2 
3 
4 
0 
1 
2 
3 
4 
0 
1 
2 
3 
4 
0 
1 
2 
3 
4 


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GP6 I feel ill 
0 
1 
2 
3 
4 
GP7 I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
not at 
a little 
some- 
quite 
very 
  
SOCIAL/FAMILY WELL-BEING 
 
all 
bit 
what 
a bit 
much 
GSI  I feel close to my fiiends 
0 
1 
2 
3 
4 
GS2  I get emotional support from my family 
0 
1 
2 
3 
4 
GS3   I get suppo11from my fiiends 
0 
1 
2 
3 
4 
GS4 My family has accepted my illness 
0 
1 
2 
3 
4 
GS5  I am satisfied with family communication about my 
0 
1 
2 
3 
4 
illness 
GS6  I feel close to my partner (or the person who is my 
0 
1 
2 
3 
4 
main supp01t) 
 
Regardless of your ClllTent level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please check the box below and go to the next section. 
□ 
GS7  I am satisfied with my sex life 
0 
1 
2 
3 
4 
  
EMOTIONALWELL-BEING 
 not at 
a little 
some- 
quite 
very 
all 
bit 
what 
a bit 
much 
GEi I feel sad 
0 
1 
2 
3 
4 
GE2 I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 I feel nervous 
0 
1 
2 
3 
4 


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GE5 I wony about dying 
0 
I 
2 
3 
4 
GE6 I wony that my condition will get worse 
0 
I 
2 
3 
4 
 
 
  
FUNCTIONALWELL-BEING 
 
not at 
a little 
some- 
quite 
very 
all 
bit 
what 
a bit 
much 
GFI I am able to work (include work at home) 
0 
I 
2 
3 
4 
GF2 My work (include work at home) is fulfilling 
0 
I 
2 
3 
4 
GF3 I am able to enjoy life 
0 
I 
2 
3 
4 
GF4 I have accepted my illness 
0 
I 
2 
3 
4 
GF5 I am sleeping well 
0 
I 
2 
3 
4 
GF6 I am enjoying the things I usually do for fun 
0 
I 
2 
3 
4 
GF7 I am content with the quality of my life right now 
0 
I 
2 
3 
4 
not at 
a little 
some- 
quite 
very 
  
ADDITIONAL CONCERNS 
 
all 
bit 
what 
a bit 
much 
H&Nl I am able to eat the foods that I like 
0 
I 
2 
3 
4 
H&N2 My mouth is dty 
0 
I 
2 
3 
4 
H&N3 I have trouble breathing 
0 
I 
2 
3 
4 
H&N4 My voice has its usual quality and strength 
0 
I 
2 
3 
4 
H&N5 I am able to eat as much food as I want 
0 
I 
2 
3 
4 


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H&N6 I am unhappy with how my face and neck look 
0 
I 
2 
3 
4 
H&N7 I can swallow naturally and easily 
0 
I 
2 
3 
4 
H&N8 I smoke cigarettes or other tobacco products 
0 
I 
2 
3 
4 
H&N9 I drink alcohol (e.g. beer, wine, etc.) 
0 
I 
2 
3 
4 
H&NIO I am ab le to communicate with others 
0 
I 
2 
3 
4 
H&Nl I I can eat solid foods 
0 
I 
2 
3 
4 
H&Nl 2 I have pain in my mouth, throat or neck 
0 
I 
2 
3 
4 


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APPENDIX G: AJCC STAGING SYSTEM, 7TH E DITIO N 
 
 
1) LIP AND ORAL CAVITY 
 
Patient Name/Information   
 
 
p   e c 
 _ 
 
Tumor Size    
 
 Histopa
Tytpe  olog 
 
 _ 
Laterality 
Bilateral 
Left 
Right 
 
 
DEFINITIONS: 
 
Ptimaiy Tumor (T) 
 
TX 
Ptima1y tumor cannot be assessed 
TO 
No  evidence of prima1y tumor 
Tis 
Carcinoma in situ 
Tl 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4a 
(Lip) Tumor invades through co1t ical bone, infe1ior alveolai·nerve , floor of mouth, or skin of face, i.e., chin or 
nose(l) 
T4a 
(Oral Cavity) Tumor invades through co1tical bone, into deep [extlinsic] muscle of tongue (genioglossus, 
hyoglossus, palatoglossus, and styloglossus), maxilla1y sinus, or skin of face 
T4b 
Tumor involves masticator space, pte1ygoid plates, or skull base and/or encases internal cai·otdi  ait e1y 
 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
NO 
No regional lymph node metastasis 
NI 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dnnension 
 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dnnension; or in 
multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or conti·alateral lymph 
nodes, none more than 6 cm in greatest dnnension 
N2a 
Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dnnension 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dnnension 


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N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
 
 
Distant Metastasis (M) 
 
MX 
Distant metastasis cannot be assessed 
MO 
No distant metastasis 
M1 
Distant metastasis 
 
Biopsy of metastatic site perfo1med 
y 
N 
 
Source of pathologic metastatic specimen 
 
 
 
Stage Grouping 
 
0 
Tis 
NO 
MO 
I 
Tl 
NO 
MO 
II 
T2 
NO 
MO 
III 
T3 
NO 
MO 
Tl 
Nl 
MO 
T2 
Nl 
MO 
T3 
Nl 
MO 
IVA 
T4a 
NO 
MO 
T4a 
Nl 
MO 
Tl 
N2 
MO 
T2 
N2 
MO 
T 3 
N2 
MO 
T4a 
N2 
MO 
IVB 
AnyT N3 
MO 
IVC 
T4b 
AnyT 
AnyN 
AnyN 
MO 
Ml 
 
 
Histologic Grade (G) 
 
GX 
Grade cannot be assessed 
Gl 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
G4 
Undifferentiated 
 
 
Residual Tumor (R) 
RX 
Presence of residual tumor cannot be assessed 


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RO 
No resid ual tumor 
RI 
Microscopic residual tumor 
R2 
Macroscopic residual tumor (continued) 
 
 
Additional Descriptors 
 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. 
Although they do not affect the stage grouping, they indicate cases needing separate analysis. 
 
m suffix indicates the presence of multiple prima1y tumors in a single site and is recorded in parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is perfo1med dmi ng or following initial multimodality therapy. 
The cTNM or pTNM categ01y is identified by a "y" prefix. The ycTNM or ypTNM categ01izes the extent of tumor 
actually present at the time of that examination. The "y" categorization is not an estimate of tumor p1i or to multimodality 
therapy. 
r prefix indicates a recmTent tumor when staged after a disease-free interval and is identified by the "r" prefix: rTNM. 
 
a prefix designates the stage dete1mined at autopsy: aTNM. 
Prognostic Indicators (if applicable) 
Notes 
 
Superficial erosion alone of bone/tooth socket by gingival primaiy is not sufficient to classify as T4. 
 
Additional Desc1iptors 
o 
Lymph-Vascular Invasion (LVI) 
o 
Lymph-Vascular Invasion Not Present (absent)/Not Identified 
o 
Lymph-Vasculai·Invasion Present/Identified 
o 
Not Applicable 
o 
Unknown/Indete1min ate 
 
 
 
 
Physician's Signatme 
  
 
Date ------------ 


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2. PHARYNX (INCLUDING BASE OF TONGUE, SOFT PALATE, AND UVULA) 
Patient Name/Information    
 
Type of Specimen    
 
 
Tumor Size    
 
Histopathologic Type  
_ 
 
Lartilty 
Bilateral 
Left 
Right 
 
DEFINITIONS: 
Prima1y Tumor (T) 
TX 
Primaiy tumor cannot be assessed 
TO 
No evidence of  prima1ytumor 
Tis 
Carcinomain situ 
 
Nasophaiynx 
Tl 
Tmnor confined to the nasophaiynx or tumor extends to orophaiynx and/or nasal cavity without pai·apha1yngeal 
extension 
T2 
Tumor with pai·aphaiyngeal extension 
T3 
Tumor involves bony stmctmes of skullbase and/orpai·ansaal sinuses 
T4 
Tmnor with intracranial extension and/or involvement of cranial nerves, hypoprhaiynx, orbit, or with extension to 
the infratemporal fossa/masticator space 
 
 
Orophatynx 
 
Tl 
Tmnor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4a 
Moderately Advanced Disease 
Tumor invades the la1ynx, extrinsic muscle of tongue, medial pte1y goid, hai·d palate , or mandible 
T4b 
Vety Advanced Disease 
Tumor invades lateral pte1ygoid muscle, pte1ygoid plates, lateral nasophaiynx, or skull base or encases cai·otid 
a1tery 
 
Hypopha1ynx 
Tl 
Tumor limited to onesubsite of hypophaiynx and 2 cm or less in greatest dimension 
T2 
Tmnor invades more than one subsiteofhypophaiynx or an adjacent site, or measmes more than 2 cm but not 
more than 4 cm in greatest diameter without fixation of hemila1ynx 
T3 
Tumor measures more than 4 cm in greatest dimension or with fixation of hemilaiynx 
T4a 
Moderately Advanced Disease 


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CONFIDENIATL 
 
 
 
 
Tumor invades thyroid/cricoid cru.tilage , hyoid bone, thyroid gland, esophagus or central compru.tm ent soft 
tissue(2) 
T4b 
Ve1y Advanced Disease 
Tmnor invades prevertebral fascia, encases carotid ru.te1y , o r in vo lves mediastinal strnctures 
Regional Lymph Nodes (N) 
Nasophru.ynx 
NX 
Regional lymph nodes caJ.lllot be assessed 
NO 
No regional lymph node metastasis 
Nl 
 Unilateral metastasis in ce1vical lymph node(s), 6 cm or less in greatest dimension, above the supraclavicular 
fossa(3) (continued) 
 
2. PHARYNX (INCLUDING BASE OF TONGUE, SOFT PALATE, AND UVULA) (continued) 
N2 
 Bilateral metastasis in cervical lymph node(s), 6 cm or less in greatest dimension, above the supraclaviculru.· 
fossa(3) 
N3 
Metastasis in a lymphnode(s) >6 cm and/or to supraclaviculru·. fossa 
N3a 
Greater than 6 cm in dimension 
N3b 
Extension to the supraclavicular fossa(3) 
 
 
Orophru.ynx and H ypop h a1ynx 
 
NX 
Regional lymph nodes cannot be assessed 
NO 
No regional lymph node metastasis 
NI 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in 
multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension 
N2a 
Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension 
N3 
Metastasis in a lymph node more than 6 cm in greatest dimension 
 
Distant Metastasis (M) 
MX 
Distant metastasis cannot be assessed 
MO 
No distant metastasis 
Ml 
Distant metastasis 
Biopsy of metastatic site perfonned 
y 
N 
Source of pathologic metastatic specimen 


CTRC at UTHSCSA 
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CONFIDENTIAL 
 
 
CTRC# 11-36 
 
Januaiy 14.2015 
 
Stage G rouping:Nasopharynx 
0 
Tis 
NO 
MO 
I 
Tl 
NO 
MO 
II 
Tl 
N I 
MO 
T2 
NO 
MO 
T2 
NI 
MO 
III 
Tl 
N2 
MO 
T2 
N2 
MO 
T3 
NO 
MO 
T3 
N I 
MO 
T3 
N2 
MO 
IVA 
T4 
NO 
MO 
T4 
N I 
MO 
T4 
N2 
MO 
IVB 
AnyT N3 
MO 
IVC 
AnyT AnyN Ml 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
-106 - 
CONFIDENTIAL 
 
 
 
 
Stage Grouping: Oropharynx and Hypopharynx 
0 
Tis 
NO 
MO 
I 
Tl 
NO 
MO 
II 
T2 
NO 
MO 
III 
T3 
NO 
MO 
Tl 
NI 
MO 
T2 
NI 
MO 
T3 
NI 
MO 
IVA 
T4a 
NO 
MO 
T4a 
NI 
MO 
Tl 
N2 
MO 
T2 
N2 
MO 
T3 
N2 
MO 
T4a 
N2 
MO 
IVB 
T4b 
AnyN MO 
IVC 
AnyT 
AnyT 
N3 
AnyN 
MO 
Ml 
HistologicGrade(G) (Oropha1ynx, Hypopha1ynx) 
GX 
Grade cannot be assessed 
GI 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
G4 
Undifferentiated 
 
 
Residual Tumor (R) 
 
RX 
Presence of residual tumor cannot be assessed 
RO 
No res idual tumor 
RI 
Microscopic residual tumor (continued) 
R2 
Macroscopic residual tumor 
Additional Descriptors 
 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. 
Although they do not affect the stage grouping, they indicate cases needing separate analysis. 
 
m suffix indicates the presence of multiple p1imaiy tumors in a single site and is recorded in parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is perfonned during or following initial multimodality therapy. 
The cTNM or pTNM catego1y is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor 
actually present at the time of that examination. The "y" categorization is not an estimate of tumor prior to multimodality 
therapy. 
 
r prefix indicates a recmrnnt tumor when staged after a disease-free interval, and is identified by the "r" prefix: rTNM. 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
-107 - 
CONFIDENTIAL 
 
 
 
 
a prefix designates the stage detennined at autopsy: aTNM. 
 
 
 
Prognostic Indicators (if applicable) 
 
 
Notes 
 
1. Paraphruyngeal extension denotes posterolateral infiltration of tumor beyond the pha1yngobasilar fascia. 
 
2. Central compa1tment soft tissue includes prelruyn geal strap muscles and subcutaneous fat. 
 
3. Midline nodes are considered ipsilateral nodes. 
 
 
 
Additional Descriptors 
Lymph-Vasculru· Invasion (LVI) 
o 
Lymph-Vasculru·Invasion Not Present (absent)/Not Identified 
o 
Lymph-Vasculru·In vasion Present/Identified 
o 
Not Applic able 
o 
Unkn own/Indete1minate 
 
 
Physician's Signature 
  
 
Date ------------ 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
-108 - 
CONFIDENTIAL 
 
 
 
 
3. LARYNX 
 
Patient Name/Information    
 
                                                        
Type of Specimen    
 
Tumor Size    
 
 
HistopTtpoelog 
_ 
 
 
Lartily 
Bilateral 
Left 
Right 
 
 
 
DEFINITIONS: 
 
Primaiy Tumor (T) 
TX 
Primaiy tumor cannot be assessed 
TO 
No evidence of  prima1ytumor 
Tis 
Carcinoma in situ 
 
Supraglottis 
Tl 
Tmnor limited to one subsite of supraglottis with normal vocal cord mobility 
T2 
 Tmnor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the 
supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyrifmm sinus) without fixation of the 
laiynx 
T3 
 Tumor limited to laiynx with vocal cord fixation and/or invades any of the following: postcricoid ai·ea, pre- 
epiglottic tissues, pai·aglottic space, and/or minor thyroid caitilage erosion (e.g., inner cmtex) 
T4a 
Moderately Advanced Local Disease 
Tumor invades through the thyroid ca1tilage and/or invades tissues beyond the la1ynx (e.g. , trachea , soft tissues of 
neck including deep extiinsic muscle of the tongue, strap muscles, thyroid, or esophagus) 
T4b 
Ve1y Advanced Local Disease 
Tumor invades preve1tebral space, encases carotid a1te1y, or invades mediastinal strnctures 
 
Glottis 
Tl 
Tumor limited to the vocal cord(s) (may involve ante1ior or posterior commissure) with nom1almobility 
Tl a 
Tumor limited to one vocal cord 
Tl b 
Tumor involves both vocal cords 
T2 
Tumor extends to supraglottis and/or subglottis, or with impaired vocal cord mobility 
T3 
 Tumor limited to the laiynx with vocal cord fixation, and/or invades paraglottic space, and/or minor thyroid 
ca1tilage erosion (e.g., inner co1tex) 
T4a 
Moderately Advanced Local Disease 
Tumor invades through the thyroid ca1tilage and/or invades tissues beyond the la1ynx(e.g., trachea, soft tissues of 
neck including deep extiinsic muscle of the tongue, strap muscles, thyroid, or esophagus) 
T4b 
Ve1y Advanced Local Disease 
Tumor invades preve1tebral space, encases carotid a1te1y, or invades mediastinal strnctures 
Subglottis 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
-109 - 
CONFIDENTIAL 
 
 
 
 
Tl 
Tumor limited to the subglottis 
T2 
Tumor extends to vocal cord(s) with n01mal or impaired mobility 
T3 
Tumor limited to laiynx: with vocal cord fixation (continued) 
T4a 
Moderately Advanced Local Disease 
Tumor invades cricoid or thyroid caitilage and/or invades tissues beyond the la1ynx: (e.g., trachea, soft tissues of 
neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) 
T4b 
Ve1y Advanced Local Diseas e 
Tumor invades prevertebral space, encases cai·otid ait e1, y  or invades mediastinal stm ctures 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
NO 
No reg ional lymph node metastasis 
NI 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in 
multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension 
N2a 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension 
N3 
Metastasis in a lymph node, more than 6 cm in greatest dimension 
 
Distant Metastasis (M) 
MO 
No distant metastasis 
Ml 
Distant metastasis 
Biopsy of metastatic site pe1f01med 
y 
N 
Source of pathologic metastatic specimen 
Stage Grouping 
0 
Tis 
NO 
MO 
I 
Tl 
NO 
MO 
II 
T2 
NO 
MO 
III 
T3 
NO 
MO 
Tl 
NI 
MO 
T2 
NI 
MO 
T 3 
NI 
MO 
IVA 
T4a 
NO 
MO 
T4a 
NI 
MO 
Tl 
N2 
MO 
T2 
N2 
MO 
T3 
N2 
MO 
T4a 
N2 
MO 
IVB 
T4b 
AnyN MO 
An y T N3 
MO 
IVC 
An y T AnyN Ml 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
- 110 - 
CONFIDENTIAL 
 
 
 
 
Histologic Grade (G) 
GX 
Grade cannot be assessed 
GI 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
G4 
Undifferentiated 
 
Residual Tumor (R) 
RX 
Presence of residual tumor cannot be assessed 
RO 
No residual tumor 
RI 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Additional Descriptors 
For identification of special cases ofTNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. 
Although they do not affect the stage grouping, they indicate cases needing separate analysis. 
m suffix indicates the presence of multiple prima1y tumors in a single site and is recorded in parentheses: pT(m)NM. 
y prefix indicates those cases in which classification is performed during or following initial multimodality therapy. 
The cTNM or pTNM catego1y is identified by a "y" prefix. The ycTNM or ypTNM catego1izes the extent of tumor 
actually present at the time of that examination. The "y" categorization is not an estimate of tumor p1ior to multimodality 
therapy. 
r prefix indicates a recmTent tumor when staged after a disease-free interval, and is identified by the "r" prefix: rTNM. 
a prefix designates the stage detennined at autopsy: aTNM. 
Prognostic Indicators (if applicable) 
Notes 
 
Additional Desc1iptors 
Lymph-Vascular Invasion (LVI) 
o 
Lymph-Vascular Invasion Not Present (absent)/Not Identified 
o 
Lymph-Vascular Invasion Present/Identified 
o 
Not Applicable 
o 
Unknown/Indeterminate 
 
Physician's Signature 
  
 
Date ------------ 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
- 111 - 
CONFIDENTIAL 
 
 
 
 
4. NASAL CAVITY AND PARANASAL SINUSES 
Patient Name/Information    
 
 
Type of Specimen  
_ 
T
um
Sioe 
 
 
HistopTt p    elog 
_ 
 
LatieralBilateral 
Left 
Right 
 
 
DEFINITIONS: 
Primaiy Tumor (T) 
Maxillaiy SinusTl 
Tumor limited to the maxillaiy sinus mucosa with no erosion or destluction of bone 
T2 
 Tumor causing bone erosion or destm ction including extension into the haid·  palate and/or middle nasal meatus, 
except extension to posterior wall of maxillaiy sinus and pte1ygoid plates 
T3 
Tumor invades any of the following: bone of the posterior wall of maxilla1y sinus, subcutaneous tissues, floor or 
medial wall of orbit, pte1ygoid fossa, ethmoid sinuses 
T4a 
Moderately Advanced Local Disease 
Tumor invades anterior orbital contents, skin of cheek, pte1ygoid plates, infratemporal fossa, cribrifo1mplate, 
sphenoid or frontal sinuses 
T4b 
Ve1y Advanced Local Diseas e 
Tmnor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial ne1ves other than 
maxillaiy division oftiigeminal nerv e V2 , nasopha1ynx , or cliv us 
 
Na sa l Cavity and Ethmoid Sinus 
TX 
Primaiy tumor cannot be assessed 
TO 
No evid en ce of pri ma1ytmnor 
Tis 
Carcinoma in situ 
Tl 
Tmnor restricted to any one subsite, with or without bony invasion 
T2 
Tmnor invading two subsites in a single region or extending to involve an adjacent region within the 
nasoethmoidal complex, with or without bony invasion 
T3 
Tmnor extends to invade the medial wall or floor of the orbit, maxillaiy sinus, palate, or cribriform plate 
T4a 
 Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior 
cranial fossa, pterygoid plates, sphenoid or frontal sinuses 
T4b 
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fos,sa cranial nerv es other than V2, 
nasopha1ynx, or clivus 
 
Regional Lymph Nodes (N) 
NX 
Regional lymph nodes cannot be assessed 
NO 
No reg ional lymph node metastasis 
NI 
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in 
multiple ipsilateral lymph nod,es none more than 6 cm in greatest dimensio, n or in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension 
N2a 
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
- 112 - 
CONFIDENTIAL 
 
 
 
 
N2b 
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymphnodes, none more than 6 cm in greatest dimension 
N3 
Metastasis in a lymphnode, more than 6 cm in greatest dimension 
 
Distant Metastasis (M) 
MO 
No distant metastasis 
Ml 
Distant metastasis 
Biopsy of metastatic site perfmmed 
y 
N 
Source of pathologic metastatic specimen 
Stage Grouping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Histologic Grade (G) 
GX 
Grade cannot be assessed 
G1 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
G4 
Undifferentiated 
 
Residual Tumor (R) 
RX 
Presence of residual tumor cannot be assessed 
RO 
No residual tumor 
Rl 
Microscopic residual tumor 
R2 
Macroscopic residual tumor 
 
Additional Desc1iptors 
For identification of special cases of TNM or pTNM classifications, the "m" suffix and "y," "r," and "a" prefixes are used. 
Although they do not affect the stage grouping, they indicate cases needing separate analysis. 
m suffix indicates the presence of multiple primaiy tumors in a single site and is recorded in parentheses: pT(m)NM. 
0 
Tis 
NO 
MO 
I 
Tl 
NO 
MO 
II 
T2 
NO 
MO 
III 
T3 
NO 
MO 
Tl 
Nl 
MO 
T2 
Nl 
MO 
T3 
Nl 
MO 
IVA 
T4a 
NO 
MO 
T4a 
Nl 
MO 
Tl 
N2 
MO 
T2 
N2 
MO 
T 3 
N2 
MO 
T4a 
N2 
MO 
IVB 
T4b 
AnyN MO 
AnyT N3 
MO 
IVC 
AnyT AnyN Ml 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
- 113 - 
CONFDI ENTIAL 
 
 
 
 
y prefix indicates those cases in which classification is perfo1med during or following initial multimodality therapy. 
The cTNM or pTNM categ01y is identified by a "y" prefix. The ycTNM or ypTNM categorizes the extent of tumor 
actually present at the time of that exalnination. The "y" categorization is not an estimate of tumor prior to multimodality 
therapy. 
r prefix indicates a recun ent tumor when staged after a disease-free interval, and is identified by the "r" prefix: rTNM. 
a prefix designates the stage detennined at autopsy: aTNM. 
Prognostic Indicators (if applicable) 
Notes 
 
Additional Descriptors 
Lymph-Vascular Invasion (LVI) 
o 
Lymph-Vascular Invasion Not Present (absent)/Not Identified 
o 
Lymph-Vascular Invasion Present/Identified 
o 
Not Applicable 
o 
Unknown/Indete1minate 
 
Physician's Signature 
  
 
Date ------------ 


CTR C at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
- 114 - 
CONFIDENTIAL 
 
 
 
 
APPENDIX H: GENENTECH SAFETY REPORTING FAX COVER SHEET 


CTRC at UTHSCSA 
CTRC# 11-36 
Januaiy 14. 2015 
 
 
 
 
 
 
Genentech 
B I O 
N CO L OG Y 
SAFETY REPORTING FAX COVER SHEET 
Investigator Sponsored Trials 
 
SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Study Number 
(Genentech studv number} 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
I 
 
 
 
 
 
Subject Initials 
(Please enter a dash If the patienthasno 
middle name 
 
 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT 
BEHIND THIS COVER SHEET 
 
 
Please contact Genentech Safety for any questions regarding 
SAE or Safety reporting at (888) 835-2555 
 
 
 
 
Page 1of_ 
 
 
Version July 2007 
I nit ial Report Date 
(DD/MON/YYYY) 
  
 
/ 
/ 
_ 
Follow-up Report Date 
(DD/ MON/ YYYY) 
_/ 
/