A Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
Phase: PHASE3
Conditions: Neck Squamous Cell Carcinoma of Unknown Primary, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Laryngeal Verrucous Carcinoma, Recurrent Lip and Oral Cavity Squamous Cell Carcinoma, Recurrent Neck Squamous Cell Carcinoma of Unknown Primary, Recurrent Oral Cavity Verrucous Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Recurrent Salivary Gland Carcinoma, Recurrent Sinonasal Squamous Cell Carcinoma, Salivary Gland Squamous Cell Carcinoma, Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7, Stage IV Major Salivary Gland Cancer AJCC v7, Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Laryngeal Verrucous Carcinoma AJCC v7, Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVA Major Salivary Gland Cancer AJCC v7, Stage IVA Oral Cavity Cancer AJCC v6 and v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Sinonasal Squamous Cell Carcinoma AJCC v7, Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Laryngeal Verrucous Carcinoma AJCC v7, Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVB Major Salivary Gland Cancer AJCC v7, Stage IVB Oral Cavity Cancer AJCC v6 and v7, Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Sinonasal Squamous Cell Carcinoma AJCC v7, Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVC Laryngeal Verrucous Carcinoma AJCC v7, Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVC Major Salivary Gland Cancer AJCC v7, Stage IVC Oral Cavity Cancer AJCC v6 and v7, Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVC Sinonasal Squamous Cell Carcinoma AJCC v7, Tongue Carcinoma
Sponsor: National Cancer Institute (NCI)

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ii 
Enclosure 
CC: Athanassios Argiris, M.D. 
Panayiotis Savvides, M.D. 
Barbara Burtness, M.D. 
Shuli Li, Ph.D. 
Michelle Catalano, Pharm.D. 
Barbara Yim, Pharm.D, BCOP 
Joe Weber 
Becky Fillingham 
 
Carol Chami, R.N. 
Melinda Flood 
Bruce Giantonio, M.D. 
Robert L. Comis, M.D. 
Donna Marinucci 
Jean MacDonald 
Mary Steele 
Kerry Higgins 
Julianne Burns 
Michael Balco 
Kevin Pollard  
Sally Vanture 
Lauren Lambert 
 
 
 

 
E1305 
1 
 
 
A Phase III Randomized Trial of Chemotherapy With or 
Without Bevacizumab in Patients with Recurrent or 
Metastatic Head and Neck Cancer  
 
STUDY CHAIR: 
Athanassios Argiris, M.D. 
 
STUDY CO-CHAIR: 
Panayiotis Savvides, M.D. 
Rev. 12/11, 7/14 
STUDY STATISTICIAN: 
Shuli Li, Ph.D. 
 
HEAD AND NECK COMMITTEE CHAIR: 
Barbara Burtness, M.D. 
Rev. 7/14 
LABORATORY CO-CHAIR: 
Athanassios Argiris, M.D. 
Version Date:  September 9, 2016 
NCI Update Date: November 20, 2013 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology  
August 8, 2008 
NRG / NRG ONCOLOGY 
 
Addendum #1 – Incorporated prior to activation 
SWOG / SWOG 
 
Update #1 – Incorporated prior to activation 
 
 
Addendum #2 – 1/09 
 
 
Update #2 – 3/09 
 
 
Update #3 – 4/09 
 
 
Addendum #3 – 12/09 
 
 
Addendum #4 – 10/10 
 
 
Addendum #5 – 1/11 
NCI Supplied Agent: 
 
Addendum #6 – 9/11 
Bevacizumab (NSC#704865, IND#113916) 
 
Addendum #7 – 11/11 
 
 
Update #4 – 11/11 
 
 
Addendum #8 – 12/11 
 
 
 
Addendum #9 – 5/12 
 
 
 
Addendum #10 – 10/12 
 
 
 
Update #5 – 11/13 
 
 
 
Addendum #11 – 7/14 
 
 
 
Addendum #12 – 8/14 
 
 
 
Addendum #13 – 1/15 
 
 
 
Addendum #14 – 10/16 
 
Rev. 7/14 
Rev. 8/14 

ECOG-ACRIN 
E1305 
Cancer Research Group 
Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
2 
Table of Contents 
Schema ................................................................................................................. 6 
1. Introduction ................................................................................................... 8 
1.1 Head and Neck Cancer .......................................................................... 8 
1.2 Docetaxel .............................................................................................. 9 
1.3 Angiogenesis and Bevacizumab in Solid Tumors and SCCHN ................ 10 
1.4 Study Rationale ................................................................................... 16 
1.5 Gender and Ethnicity Statement ......................................................... 17 
2. Objectives .................................................................................................... 18 
2.1 Primary Objective................................................................................ 18 
2.2 Secondary Objectives .......................................................................... 18 
3. Selection of Patients ..................................................................................... 19 
4. Randomization Procedures ........................................................................... 24 
4.1 Randomization to Arm A or Arm B ....................................................... 26 
4.2 Eligibility Verification........................................................................... 27 
4.3 Additional Requirements ..................................................................... 27 
4.4 Stratification Factors ........................................................................... 27 
4.5 Instructions for Patients Who Do Not Start Assigned Protocol Treatment27 
5. Treatment Plan ............................................................................................. 28 
5.1 Treatment - Arm A .............................................................................. 28 
5.2 Treatment Arm B (with bevacizumab) ................................................. 32 
5.3 Adverse Event Reporting Requirements .............................................. 34 
5.4 Comprehensive Adverse Events and Potential Risks List (CAEPR) For 
Bevacizumab  (rhuMAb, VEGF, NSC 704865) ....................................... 44 
5.5 Dose Modifications ............................................................................. 50 
5.6 Prophylactic Medication Regimen ....................................................... 67 
5.7 Supportive Care .................................................................................. 68 
5.8 Management Of Docetaxel Adverse Events ......................................... 69 
5.9 Duration of Therapy ............................................................................ 72 
5.10 Duration of Follow-up ......................................................................... 72 
6. Measurement of Effect ................................................................................. 73 
6.1 Solid Tumor Response Criteria (RECIST) ............................................... 73 
6.2 Evaluation of Patient's Best Overall Response ..................................... 75 
7. Study Parameters ......................................................................................... 78 
7.1 Therapeutic Parameters ...................................................................... 78 
7.2 Biological Sample Submissions ............................................................ 80 
8. Drug Formulation and Procurement ............................................................. 81 
8.1 Bevacizumab (NSC 704865) ................................................................. 81 
8.2 Docetaxel  - (Please refer to the package insert for further information)83 
8.3 Cisplatin (Cis-Diaminedichloroplatinum, CDDP) ................................... 88 
8.4 5-Fluorouracil ...................................................................................... 89 

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
3 
8.5 Carboplatin ......................................................................................... 90 
9. Statistical Considerations .............................................................................. 94 
9.1 Objectives ........................................................................................... 94 
9.2 Randomization .................................................................................... 94 
9.3 Accrual ................................................................................................ 94 
9.4 Data monitoring and early stopping rules ............................................ 94 
9.5 Early Stopping for Excessive Toxicity.................................................... 95 
9.6 Gender and Ethnicity ........................................................................... 95 
9.7 Study Monitoring ................................................................................ 96 
10. Correlative Studies ....................................................................................... 97 
10.1 Sample Submissions ............................................................................ 97 
10.2 Biomarkers of Bevacizumab Activity .................................................. 102 
10.3 Biomarkers to Predict Chemotherapy and Bevacizumab Toxicity ....... 102 
10.4 Banking ............................................................................................. 102 
10.5 Sample Inventory Submission Guidelines .......................................... 102 
10.6 Lab Data Transfer Guidelines ............................................................. 103 
11. Records to Be Kept ..................................................................................... 104 
11.1 Records Retention ............................................................................. 104 
12. Patient Consent and Peer Judgment ........................................................... 104 
13. References ................................................................................................. 104 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Update #5]............................................................... 107 
Appendix II  Pathology Submission Guidelines ................................................... 108 
 Appendix III  Patient Thank You Letter .............................................................. 113 
 Appendix IV  Cancer Trials Support Unit (CTSU) Participation Procedures  [Deleted 
in Addendum #11] ...................................................................................... 114 
Appendix V  E1305 Collection and Shipping Kit Order Form ............................... 115 
Appendix VI  E1305 Shipping Notification Form ................................................. 116 
Appendix VII  Cooperative research and Development Agreement (CRADA)...... 117 
Appendix VIII  ASCO 2006 Antiemetic Guidelines .............................................. 119 
Appendix IX  New York Heart Association (NYHA) Classification ........................ 120 
 

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
4 
 
STUDY CHAIR 
STUDY CO-CHAIR 
Athanassios Argiris, MD 
UT Health Science Center at San Antonio 
Cancer Therapy & Research Center 
7979 Wurzbach Road MC8232 
Zeller Building- 4th Floor, Room Z418 
San Antonio, TX 78229 
Phone number: 210-450 3838 
Fax number: 210-692 7502 
E-mail: athanassios.argiris@gmail.com 
 
Panayiotis (Panos) Savvides, MD, PhD, 
MPH 
The Ohio State University  
Comprehensive Cancer Center 
The Ohio State University's  
Wexner Medical Center 
Columbus, OH 43210 
Tel: 614-293-9868 
Fax: 614-366-9431 
E-mail: panos.savvides@osumc.edu 
 
STUDY CHAIR LIAISON (SCL) 
Ofelia Romero 
UT Health Science Center 
7979 Floyd Curl, MC 8032 
San Antonio, TX 78229 
Tel: 210-450-1810 
Fax: 210-614-4418 
E-mail: romeroo@uthscsa.edu  
 
 
Rev. 11/11, 11/13 
Rev. 7/14 

ECOG-ACRIN 
E1305 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site pre-
registration documents: 
For patient enrollments:  
Submit study data directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.
org (for submitting regulatory 
documents only) 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations Office - 
Boston, 
FSTRF, 900 Commonwealth 
Avenue, Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal 
mail (preferred), however fax is 
accepted. 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at:  https://www.ctsu.org 
 
Rev. 7/14 

ECOG-ACRIN 
E1305 
Cancer Research Group 
Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
6 
Schema 

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
7 
 
Recurrent or Metastatic SCCHN
Stratify by:
1) PS 0-1 (Performance Status)
2) Weight loss
3) Prior radiation to head and neck
4) Chemo Regimen
Arm A
Platinum-doublet*
Every 21 days until disease 
progression
Arm B
Bevacizumab 15 mg/kg IV, day 1
Platinum-doublet*
Every 21 days until disease 
progression
Cycle = 21 days
Accrual goal = 400 patients
All doses will be based on patient’s actual weight. 
R
A
N
D
O
M
I
Z
E
Option to discontinue 
chemotherapy after 6 cycles if 
maximum response.  Bevacizumab 
will be continued until progression.
Physician Choice 
of Chemotherapy 
Regimens*
Option to discontinue 
chemotherapy after 6 cycles if 
maximum response.
Rev. 10/10
* Chemotherapy regimen choices: 4 options
Regimen 1:
Docetaxel 75 mg/m2 IV over 1 hour, day 1, followed by Cisplatin 75 mg/m2 IV over 1-2 hours, day 1,every 21 days. Prophylactic ciprofloxacin 500 mg twice daily, orally, on 
days 5-14.
Regimen 1 carbo:
Docetaxel 75 mg/m2 IV over 1 hour, day 1, followed by Carboplatin AUC 6 over 30 min., day 1, every 21 days. Prophylactic ciprofloxacin 500 mg twice daily, orally, on days 5-
14.
Regimen 2:
Cisplatin 100 mg/m2 IV over 1-2 hours on day 1, followed by 5-FU 1000 mg/m2 /day as a continuous infusion x 4 days, every 21 days. Prophylactic ciprofloxacin 500 mg twice 
daily, orally, on days 5-14.
Regimen 2 carbo:
Carboplatin AUC 6 over 30 min., day 1, followed by 5-FU 1000 mg/m2 /day as a continuous infusion x 4 days, every 21 days. Prophylactic ciprofloxacin 500 mg twice daily, 
orally, on days 5-14.
NOTE:
Chemotherapy regimen choice will be at the discretion of the treating physician and will be made prior to randomization. See Section 5 for additional information regarding the 
chemotherapy regimen choices.
NOTE:
If maximum response, option to discontinue chemotherapy treatment after 6 cycles.
Rev. 11/11
Rev. 11/11
Rev. 11/11

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
8 
1. 
Introduction 
1.1 
Head and Neck Cancer 
Approximately 40,000 new cases of head and neck cancer are diagnosed 
annually in the United States (1).  Squamous cell carcinomas account for more 
than 90% of head and neck cancer cases. Patients with squamous cell 
carcinoma of the head and neck (SCCHN) usually present with locoregionally 
advanced disease. Initial presentation with distant metastasis may occur in about 
10% of all patients. However, recurrence of disease either in local or distant sites 
after potentially curative treatment with surgery and/or radiation with or without 
chemotherapy develops in more than 50% of patients with locoregionally 
advanced SCCHN. Therefore, the majority of patients with SCCHN develop 
recurrent or metastatic disease during the course of their illness. These patients 
have poor prognosis; their median survival is 6-9 months (2-4).  
Active single agents in SCCHN include methotrexate, bleomycin, cisplatin, 
carboplatin, 5-FU, paclitaxel, docetaxel, and CPT-11. A small randomized study 
showed that cisplatin monotherapy prolongs survival compared with best 
supportive care (5). Response rates for single agents range between 10-40% 
(2,4,6,7). Combination chemotherapy achieves higher response rates than 
monotherapy but has not been shown to produce a survival benefit compared to 
single agents in phase III randomized trials in recurrent/metastatic head and neck 
cancer (2,4).   
A phase III randomized study conducted by the SWOG compared platinum-
based combination chemotherapy to single agent methotrexate (2).  The 
objective response rates were 32%, 21%, and 10% for cisplatin/5-FU, 
carboplatin/5-FU, and single agent methotrexate, respectively, but the median 
overall survival was identical in the 3 arms.  Moreover, toxicity was increased 
with combination chemotherapy, especially with the cisplatin-based regimen. 
Another randomized study demonstrated a significantly higher response rate of 
32% for the combination of cisplatin and 5-FU versus 17% and 13% for single 
agent cisplatin and 5-FU, respectively (4). However, the median survival was 
approximately 6 months with no differences between the 3 arms. Hematologic 
toxicity was increased in the combination arm. Nevertheless, cisplatin-based 
combination chemotherapy regimens, mainly due to their higher activity, have 
been widely used for the treatment of SCCHN and have been evaluated in a 
number of subsequent phase III trials. 
Two randomized trials conducted by the ECOG (E1393 and E1395) compared 
cisplatin doublets (cisplatin/paclitaxel at two dose levels, and cisplatin/paclitaxel 
vs. cisplatin/5-FU) but failed to show any survival differences between arms. 
E1393 compared high-dose paclitaxel (200 mg/m2) as a 24-hour infusion plus 
cisplatin 75 mg/m2, with G-CSF support, to low-dose paclitaxel (135 mg/m2) as a 
24-hour infusion, plus cisplatin 75 mg/m2.8 Two-hundred-ten patients were 
randomized between the 2 arms. No significant differences in outcome were 
observed. The response rate was 35% vs. 36% and the median survival was 7.6 
months vs. 6.8 months, in the high-dose vs. low-dose paclitaxel arms, 
respectively. Substantial toxicities were observed in this trial. The toxic death rate 
was 10% (12% vs. 9%). It was concluded that the 24-hour paclitaxel infusion was 

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
9 
associated with unacceptable toxicity when combined with cisplatin. Instead a 3-
hour paclitaxel infusion combined with cisplatin was advanced to further testing.  
A more recent phase III randomized trial conducted by ECOG (E1395) compared 
the combination of paclitaxel 175 mg/m2 as a 3-hour infusion and cisplatin 75 
mg/m2 (CP) to a standard cisplatin and 5-FU (CF) regimen (3). Two hundred 
eighteen patients with recurrent or metastatic disease were randomized in one of 
the two arms. No statistically significant difference was observed either in 
response rates or survival between the two regimens 3. Estimated median 
survival was 8.7 months in the CF group and 8.1 month in the CP group. 
Objective response rate was 27% in the CF group and 26% in the CP group. 
Toxicity was generally comparable between groups, with the most frequent 
including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and 
stomatitis. However, gastrointestinal and hematological toxicities were common 
with CF. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; 
eight from infection, two from hemorrhage, one from cardiac causes and one 
from unknown causes. The incidence of common grade 3 or 4 toxicities was as 
follows in the CF vs. CP arms: neutropenia 67% versus 55%, thrombocytopenia, 
23% vs. 4%, stomatitis 31% vs. 0%, diarrhea 6% vs. 1%, sensory neuropathy 4% 
vs. 5%, fatigue 9% vs. 7%. Therefore, cisplatin/paclitaxel emerged as an 
acceptable treatment option for recurrent /metastatic SCCHN. A more recent 
randomized trial conducted by ECOG (E5397), compared cisplatin plus 
cetuximab, an active EGFR inhibitor, with cisplatin alone in patients with 
chemotherapy naïve, recurrent or metastatic head and neck cancer (8). The 
addition of cetuximab to cisplatin increased the objective response rates from 
10% to 26% (p=0.03) and the median progression-free survival from 2.7 to 4.2 
months but the latter difference did not reach statistical significance (p=0.09), 
presumably due to the relatively small sample size of the trial (116 patients total). 
Median overall survival was also longer in the cetuximab arm (9.2 vs.8 months, 
p=0.21). Further study of targeted agents in SCCHN is warranted.  
1.2 
Docetaxel 
Docetaxel is a semisynthetic taxane, derivative of 10-deacetylbaccatin III, a 
precursor extracted from the needles of the European yew, T. baccata. It acts as 
a mitotic spindle poison by promoting microtubule assembly but inhibiting tubulin 
depolymerization, which disrupts cell division. Changes in apoptotic pathways as 
well as an antiangiogenesis effect have also been demonstrated. Docetaxel is 
metabolized by the CYP3A4 isoenzyme, and its metabolism may be inhibited by 
CYP3A4 inhibitors, such as ketoconazole, erythromycin, troleandomycin, and 
nifedipine. Most clinical experience has been acquired using a dose of 75-100 
mg/m² given every 3 weeks.  The dose-limiting toxicity (DLT) with this schedule 
of administration is neutropenia.  Other toxicities caused by docetaxel include a 
fluid retention syndrome due to a capillary leak syndrome, peripheral neuropathy, 
nausea and vomiting, and hypersensitivity reactions.  Premedication with steroids 
is required to prevent hypersensitivity reactions and the fluid retention syndrome 
associated with docetaxel. Phase II studies have documented the efficacy of 
docetaxel in a variety of solid tumors, including breast, lung, ovarian and 
head/neck cancers, and gastrointestinal malignancies 

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
10 
1.2.1 
Docetaxel in SCCHN 
Docetaxel has shown activity as single agent and in combination 
regimens in head and neck cancer. Cisplatin and docetaxel have 
been combined in multiple phase II trials in SCCHN. This regimen 
demonstrated considerable activity in phase II trials in recurrent or 
metastatic SCCHN with response rates between 33-54% 9-11. Glisson 
et al evaluated cisplatin 75 mg/m2 and docetaxel 75 mg/m2, every 21 
days, in 32 patients with recurrent or metastatic SCCHN 9. They 
observed a response rate of 40%, median PFS of 4 months, and 
median survival of 9.6 months. Grade 4 neutropenia developed in 
71% of patients. Two patients (6%) experienced serious fever during 
grade 4 neutropenia (without documented infection) that required 
intravenous antibiotics, and an additional four patients had grade 3 
infection. Other severe (grades 3 and 4) toxic effects were asthenia 
(25%), nausea (11%), fever (8%), vomiting (8%), severe 
hypersensitivity reactions (8%), and diarrhea (8%). A phase III trial of 
cisplatin/docetaxel versus cisplatin/5-FU in recurrent/metastatic 
SCCHN has been conducted but results have not been reported yet. 
Although no phase III data are currently available, cisplatin and 
docetaxel is a platinum doublet that appears to be at least equally 
efficacious to cisplatin and paclitaxel. Therefore, we propose to use 
cisplatin/docetaxel or cisplatin/5-FU (investigator’s choice) as 
reference regimens for this phase III study in SCCHN and compare 
them to an experimental regimen that consists of the same 
chemotherapy regimen but with the addition of bevacizumab. 
1.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Rev. 9/11 
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1.4 
Study Rationale 
In conclusion, the systemic therapy of recurrent/metastatic head and neck cancer 
has produced disappointing results. Bevacizumab is a novel agent that targets 
VEGF and has produced promising results in multiple solid tumors. Bevacizumab 
is currently FDA approved for advanced colorectal cancer and in non-small cell 
lung cancer. We hypothesize that the addition of bevacizumab to standard 
platinum-based chemotherapy will result in survival benefit in patients with 
recurrent or metastatic SCCHN. Therefore, we propose a phase III randomized 
comparison of cisplatin/docetaxel, carboplatin/docetaxel, or carboplatin/5-FU, (or 
cisplatin/5-FU) with or without bevacizumab.  
Rev. 11/11 
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1.5 
Gender and Ethnicity Statement 
Accrual to ECOG trials for advanced head and neck (E1392, E1395, E1393) 
shows the following distribution: 14% Black non-Hispanics, 4% Hispanics, 80% 
White non-Hispanics, and 2% unknown or other. This study is open to both men 
and women of all ethnic groups and of all educational levels. Therefore, the 
enrollment pattern is expected to be similar to other ECOG-ACRIN head and 
neck cancer studies. The proportion of minorities will probably be somewhat 
higher in this study, because of recent efforts in ECOG-ACRIN to improve 
minority accrual to clinical trials. These efforts include conducting focus 
groups/workshops with community physicians affiliated with a clinical cooperative 
group developing, implementing, and marketing an outreach intervention to 
increase minority accrual. 
The reasons for shorter survivals for minorities with head and neck cancer may 
be due to delay in diagnosis, lack of adequate access to treatments, and 
response differences between ethnic groups. It is out of the scope of the study to 
assess the first two, and at present there is no data to support differences in 
responses by ethnic group. For this reason treatment assignment in the study is 
not stratified by ethnicity. Subset analyses will be conducted in this study to 
assess any potential ethnic/gender specific treatment effects and interactions 
when possible. 
 

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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To compare the overall survival of patients with recurrent or 
metastatic head and neck cancer treated with standard platinum-
based chemotherapy with or without bevacizumab. 
2.2 
Secondary Objectives 
2.2.1 
To assess toxicities with the addition of bevacizumab to each platinum 
doublet (cisplatin/docetaxel, carboplatin/docetaxel, cisplatin/5-FU, 
carboplatin/5-FU). 
2.2.2 
To compare the objective response rates, and the progression-free 
survival achieved with the above therapies. 
2.2.3 
To collect blood samples before and after therapy for future 
correlative studies. 
2.2.4 
To collect tumor tissue samples available at baseline from prior 
diagnostic procedures for future correlative studies. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. The 
checklist must be completed for each patient and must be signed and dated by the 
treating physician. Please submit the completed eligibility checklist as outlined in 
the Forms Submission Schedule, which is posted on the ECOG website with the 
protocol (www.ecog.org). A copy of the completed checklist should also be maintained 
in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. 
 
 
Patient’s Initials (L, F, M) 
 
 
Physician Signature  
 
Date 
 
NOTE: 
All questions regarding eligibility should be directed to the Study Chair or 
Study Chair Liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
3.1.1 
Patients must have histologically or cytologically confirmed Squamous 
Cell Cancer of the Head and Neck (SCCHN), from any primary site, 
including unknown primary cancers of the head and neck. Patient 
must not have nasopharyngeal carcinoma of histologic types WHO 2 
or 3 or squamous cell carcinoma that originated in the skin. 
3.1.2 
Patients must have SCCHN that is either (a) recurrent, judged 
incurable by surgery or radiation or (b) metastatic. 
NOTE: 
Patients who refuse radical resection for recurrent disease 
are eligible 
NOTE: 
A second primary squamous cell carcinoma of the head 
and neck is allowed if eligibility is based on a recurrent or 
metastatic first primary squamous cell carcinoma of the 
head and neck. 
3.1.3 
No prior chemotherapy or biologic/molecular targeted therapy for 
recurrent or metastatic SCCHN.  
3.1.3.1 
Patients may have received one regimen of induction, 
concomitant chemoradiotherapy and/or adjuvant 
chemotherapy as part of initial potential curative therapy 
but must not have received prior chemotherapy for 
recurrent or metastatic disease. 
3.1.3.2 
A minimum of 4 months is required between last dose of 
chemotherapy or chemoradiotherapy and study treatment. 
In addition patients must be progression-free for at least 4 
months after completion of chemotherapy or 
______ 
______ 
______ 
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chemoradiotherapy or radiation plus cetuximab given with 
a curative intent. (Cetuximab therapy: 4 months is required 
between last dose of chemotherapy or chemoradiotherapy 
and study treatment if part of concurrent regimen, 8 weeks 
if part of adjuvant regimen post radiation). 
3.1.3.3 
Patients having progression after 2 cycles of induction 
chemotherapy are not eligible for the study. 
3.1.4 
No prior bevacizumab is allowed. 
3.1.5 
A maximum of one prior radiotherapy regimen, curative or palliative, 
to the head and neck is allowed. If the radiation is combined with 
chemotherapy and/or cetuximab, a minimum of 4 months must elapse 
between the end of radiotherapy and registration. If the radiation is 
given alone, a minimum of 8 weeks must elapse between the end of 
radiotherapy and registration. A minimum of 3 weeks must elapse 
between prior radiation to other areas and registration. 
3.1.6 
Patients must not be receiving any other investigational agent while 
on the study. 
3.1.7 
ECOG performance status of 0-1 
3.1.8 
Patients must have recovered to grade 1 or better from any acute 
effects of prior surgery, chemotherapy, or radiation therapy, and 
should be > 4 weeks post surgery. Chronic late xerostomia, speech 
and swallowing abnormalities resulting from prior radiation or surgery 
are permitted if nutritional status is stable. 
3.1.9 
Patients must have measurable disease based on RECIST (see Sec. 
6.0). Baseline measurements and evaluations of all sites of disease 
must be obtained ≤ 4 weeks prior to randomization. Disease in 
previously irradiated sites is considered measurable if there has been 
unequivocal disease progression or biopsy-proven residual carcinoma 
following radiation therapy.  
Persistent disease after radiotherapy must be biopsy proven at least 8 
weeks after completion of radiation therapy.  (Radiographic findings 
are acceptable providing that clear-cut measurements can be made). 
3.1.10 
Baseline parameters: < 2 weeks prior to randomization 
3.1.10.1 
ANC ≥ 1500/mm3 
ANC: ___________ Date of test: ___________ 
3.1.10.2 
Hgb ≥ 8.0 g/dL 
Hgb: ___________ 
Date of test: ___________ 
3.1.10.3 
Platelet count ≥ 100,000/mm3  
Platelet count: ___________ Date of test: ___________ 
3.1.10.4 
Creatinine clearance of ≥ 60 ml/min. 
Creatinine: ___________ 
Date of test: ___________ 
______ 
______ 
______ 
Rev. 1/09, 
12/09, 10/12 
______ 
______ 
______ 
______ 
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Creatinine clearance may be measured or calculated. If 
calculating, creatinine clearance, use the Cockroft-Gault 
formula:  
(140 – Pt. age) x (Pt. weight in kg) (for females, multiply the result by 0.85) 
72 x patient’s serum creatinine 
Actual not ideal, body weight will be used. 
3.1.11 
Total bilirubin within normal limits (must be obtained ≤ 2 weeks prior 
to randomization): 
ULN:________ Total Bilirubin:_______   Date of test: ___________ 
AST or ALT and Alkaline Phosphatase must be within the range 
allowing for eligibility, as determined by the table below. 
Alkaline phosphatase, SGOT (AST) and SGPT (ALT) values must be 
obtained ≤ 2 weeks prior to randomization 
ULN: ________  AST/ALT*:_______  Date of test: ___________ 
ULN: ________  Alk Phos:________  Date of test: ___________ 
 
AST or ALT:* 
ALK PHOS: 
£ ULN 
>1x but £1.5x  >1.5x but £5x  >5x ULN 
£ ULN 
Eligible 
Eligible 
Eligible 
Ineligible 
>1x but £2.5x  
Eligible 
Eligible 
Ineligible 
Ineligible 
>2.5x but £5x  
Eligible 
Ineligible 
Ineligible 
Ineligible 
>5x ULN 
Ineligible 
Ineligible 
Ineligible 
Ineligible 
*AST/ALT level is based upon more abnormal of the two 
3.1.12 
Urine dipstick must be ≤ 0-1+ within 2 weeks (14 days) of 
randomization. If urine dipstick result is > 1+, a calculation of Urine 
Protein Creatinine (UPC) ratio is required. Patients must have a UPC 
ratio < 1.0 to participate in the study. 
Urine protein ≤ 1+ by urine dipstick? ____  
(Yes or No) Urine protein ____ Date of test _____ 
If urine protein > 1+, UPC < 1? ____  
(Yes or No) UPC ratio____ Date of test _____ 
NOTE: 
UPC ratio of spot urine is an estimation of the 24 urine 
protein excretion – a UPC ratio of 1 is roughly equivalent to 
a 24-hour urine protein of 1 gm. UPC ratio is calculated 
using one of the following formulas: 
- [urine protein]/[urine creatinine] – if both protein and 
creatinine are reported in mg/Dl 
- [(urine protein) x0.088]/[urine creatinine] – if urine 
creatinine is reported in mmol/L 
______ 
______ 
Rev. 3/09, 
10/10 
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3.1.13 
No known brain metastases. 
3.1.14 
Patients who meet the following criteria will be excluded due to the 
possibility of increased risk for tumor bleeding with bevacizumab 
therapy: 
• 
tumors that invade major vessels (e.g. the carotid) as shown 
unequivocally by imaging studies, 
• 
central (i.e. within 2 cm from the hilum) lung metastases that are 
cavitary as shown unequivocally by imaging studies,  
• 
any prior history of bleeding related to the current head and neck 
cancer, 
• 
history of gross hemoptysis (bright red blood of ½ teaspoon or 
more per episode of coughing) ≤ 3 months prior to enrollment. 
3.1.15 
No history of coagulopathy or hemorrhagic disorders. 
3.1.16 
Patients should not have a history of thrombosis (e.g. pulmonary 
embolism or deep venous thrombosis) currently requiring therapeutic 
anticoagulation (prophylactic use of warfarin 1 mg per day is allowed) 
and INR should be < 1.5 at registration. 
3.1.17 
Patients must not be receiving chronic daily treatment with aspirin  
(> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAID’s) 
known to inhibit platelet function. The use of anti-platelet agents (e.g. 
dipyridamole (Persatine), ticlopidine (Ticlid), clopidogrel (Plavix)) is 
allowed only if patient is not receiving aspirin or NSAID’s known to 
inhibit platelet function. 
3.1.18 
No hypercalcemia related to head and neck cancer. 
3.1.19 
Patients with a prior history of squamous cell or basal carcinoma of 
the skin or in situ cervical cancer must have been curatively treated. 
Patients with a history of other prior malignancy must have been 
treated with curative intent and must have remained disease-free for 3 
years post diagnosis. 
3.1.20 
No current peripheral neuropathy ≥ grade 2 at time of randomization. 
3.1.21 
Patients must not have any co-existing condition that would preclude 
full compliance with the study. 
3.1.22 
No prior history of severe hypersensitivity reaction to Docetaxel or 
other drugs formulated with polysorbate 80, if the physician’s choice 
of chemotherapy regimen is docetaxel.  
3.1.23 
All patients must have blood pressure ≤ 150/90 ≤ 2 weeks prior to 
randomization. Patients with history of hypertension must be well-
controlled upon study entry (≤ 150/90) on a stable regimen of anti-
hypertensive therapy. 
3.1.24 
No major surgical procedure, open biopsy, or significant traumatic 
injury within 28 days prior to study enrollment, or anticipation of need 
for major surgical procedure during the course of the study. 
3.1.25 
No unstable angina or myocardial infarction within the previous 6 
months; no symptomatic congestive heart failure, New York Heart 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
______ 
Rev. 10/10 
Rev. 1/11 
Rev. 11/11 
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Rev. 10/10 
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NCI Update Date: November 20, 2013 
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Association (NYHA) Grade II or greater (see Appendix IX); no history 
of aortic dissection or presence of aneurysm > 6 cm (or at high risk for 
rupture); no serious cardiac arrhythmia requiring medication (history 
of chronic atrial fibrillation or other atrial arrhythmia with controlled 
rate on medication is allowed); no clinically significant peripheral 
vascular disease manifested by intermittent claudication or need for 
vascular intervention; no history of aortic dissection; no history of any 
CNS cerebrovascular ischemia or stroke within the last 6 months; no 
active serious infection. 
3.1.26 
Patients should not have prior history of a serious human anti-human 
antibody (HAHA) reaction. Patients with known hypersensitivity to 
Chinese hamster ovary cell products or other recombant human 
antibodies are not eligible. 
3.1.27 
Age ≥ 18 years. Because no dosing or adverse event data are 
currently available on the use of bevacizumab in patients < 18 years 
of age, children are excluded from this study. 
3.1.28 
Women must not be pregnant or breast feeding because 
chemotherapy may be harmful to the fetus or the nursing infant. 
Pregnant women are excluded from this study because chemotherapy 
and/or bevacizumab have the potential for teratogenic or abortifacient 
effects. Women of child-bearing potential and men must agree to total 
abstinence or to use adequate hormonal or barrier method of birth 
control prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while 
in this study, she should inform her treating physician immediately. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to randomization to rule out pregnancy. 
Female? ___________ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.29 
HIV-positive patients receiving combination anti-retroviral therapy are 
excluded from the study because of possible drug interactions with 
study drugs. Appropriate studies will be undertaken in patients 
receiving combination anti-retroviral therapy when indicated.  
3.1.30 
No history of abdominal fistula, gastrointestinal perforation, or intra-
abdominal abscess within 6 months prior to registration. 
 
______ 
______ 
______ 
______ 
______ 
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4. 
Randomization Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
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at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
Downloading Site Registration Documents   
Site registration forms may be downloaded from the E1305 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E1305 
• 
Click on the Site Registration Documents link 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206 
E-MAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE: 
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing by 
the investigator and approved by the IRB. 
3. 
A. 
CTSU IRB Certification Form. 
Or 
B. 
HHS OMB No. 0990-0263 (Replaces Form 310). 
Or 
C. 
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review 
• 
Signature of IRB official 

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Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-
IAM username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within ten working days after randomization.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To 
access OPEN, the site user must have an active CTEP-IAM account (check at < 
https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or 
participating organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA authorization 
form (if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
NOTE: 
To receive site reimbursement for specific tests and/or bio-specimen 
submissions, completion dates must be entered in the OPEN Funding screen 
post registration. Please refer to the protocol specific funding page on the 
CTSU members’ website for additional information. Timely entry of 
completion dates is recommended as this will trigger site reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Randomization to Arm A or Arm B 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
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4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials and chart number 
4.1.3.2 
Patient’s Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Sex 
4.1.3.3.2 
Birth date (mm/yyyy) 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. An 
eligibility checklist has been appended to the protocol. A confirmation of 
registration will be forwarded by the ECOG-ACRIN Operations Office – Boston. 
4.3 
Additional Requirements  
4.3.1 
All patients must provide a signed and dated, written informed 
consent form. 
4.3.2 
To participate, a site must have IRB approval of a consent form that 
permits the patient to either agree to or opt-out of the optional 
correlative research studies and tissue banking. All patients must be 
presented with a consent form which provides them the opportunity to 
authorize collection, banking and future use by the investigator 
4.3.3 
Samples for correlative studies or banking are to be submitted as 
indicated in Section 10. 
4.4 
Stratification Factors 
4.4.1 
Chemotherapy combination (cisplatin/docetaxel vs 
carboplatin/docetaxel vs cisplatin/5-FU vs carboplatin/5-FU) 
4.4.2 
Performance status (0 vs 1) 
4.4.3 
Prior radiation to the head and neck. 
4.4.4 
Weight loss < 5% vs. ≥ 5% of total body weight in the last 6 months. 
4.5 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
If the patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E1305 Forms packet. Document the reason for not starting 
protocol treatment on the off-treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives. 
 
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5. 
Treatment Plan 
At the discretion of the investigator patients will receive 1 of 4 regimens, i.e. 
Cisplatin/Docetaxel (regimen 1), Carboplatin/Docetaxel (regimen 1 carbo), Cisplatin/5-
FU (regimen 2) or Carboplatin/ 
5-FU (regimen 2 carbo) (selection will be made prior to randomization).  
Patients in Arm A will NOT receive bevacizumab. Patients in Arm B will receive 
bevacizumab (in addition to the investigator’s selected chemotherapy). 
All dose calculations will be based on the patient’s actual weight. 
5.1 
Treatment - Arm A  
Investigators may choose one of 4 regimens (regimen 1, 1 carbo, 2, or 2 
carbo) at registration and prior to randomization. 
Regimen 1A: Docetaxel + Cisplatin 
Regimen 1A carbo: Docetaxel + Carboplatin 
Regimen 2A: Cisplatin + 5-FU 
Regimen 2A carbo: Carboplatin + 5-FU 
5.1.1 
Regimen 1A (Docetaxel + Cisplatin) 
Docetaxel 75 mg/m2 IV over 1 hour, day 1, followed by 
Cisplatin 75 mg/m2 IV over 1-2 hours, day 1 
Every 21 days 
Prophylactic ciprofloxacin 500 mg twice daily, orally, on days 5-14 
For Docetaxel: Dexamethasone 8 mg orally, twice a day, starting the 
night (i.e. approximately 12 hours prior to docetaxel) prior to docetaxel 
for a total of 6 doses (see 5.1.1.2 for additional antiemetic 
dexamethasone treatment). On the day docetaxel is given, a higher 
dose of dexamethasone (10-20 mg) is recommended as part of 
antiemetic therapy. 
Continue regimen until progression. Treatment may be discontinued if 
there is maximum response (i.e., no improvement in tumor 
measurements for 2 or more cycles) after cycle 6. 
If patients develop specific intolerable cisplatin-associated toxicities 
(see dose modifications, carboplatin substitution), such as 
neuropathy, renal impairment, ototoxicity, or nausea/vomiting, 
carboplatin at an AUC of 6 will be substituted for cisplatin. 
5.1.1.1 
Cisplatin will require aggressive hydration. Any preexisting 
dehydration should be corrected.  
Hydration Requirements 
Hydration guidelines may be modified at the discretion of 
the treating physician provided adequate pre and post 
cisplatin hydration is achieved and renal function remains 
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adequate. One suggested regimen consists of 
administering cisplatin in 500 cc to 1000 cc of IV fluids 
following adequate hydration and the establishment of 
adequate urinary output. It is suggested the pre-cisplatin 
hydration consist of NS at 500 cc/hr x 1 liter and post-
cisplatin hydration consist of 1/2 NS + 10 meq KCl/liter + 1 
gram magnesium sulfate/liter + 25 grams mannitol/liter at 
500 cc/hr for at least one hour, followed by additional 
hydration at the discretion of the investigator. 
5.1.1.2 
Antiemetics  
It is suggested that patients receive antiemetic therapy, 
acute and delayed, including dexamethasone, 5-HT3 
serotonin receptor antagonists and aprepitant, according to 
published ASCO guidelines (see Appendix VIII). However, 
the specifics of the regimen are at the discretion of the 
treating physician, provided adequate control is achieved. 
One potential regimen consists of 20 mg of oral or IV 
dexamethasone and a high dose of oral or IV 5-HT3 
antagonist (such as 2 mg oral or 10 mcg/kg IV granisetron, 
or 32 mg oral or IV ondansetron) on the day of cisplatin 
administration. Followed by additional anti-emetics 
consisting of oral dexamethasone and scheduled 5-HT3 
serotonin receptor antagonists on days 2-5. For example, 8 
mg orally, twice daily for days 2 and 3, and then 4 mg 
orally, twice daily for days 4 and 5, especially if aprepitant 
is not given. Aprepitant should be used with caution when 
combined with docetaxel due to the possibility of a drug 
interaction with docetaxel via CYP3A4 pathway. On the 
day of chemotherapy administration, the dose of 
dexamethasone must be reduced by 50%, if aprepitant is 
given. 
5.1.2 
Regimen 1A carbo (Carboplatin/Docetaxel) 
Docetaxel 75 mg/m2 IV over 1 hour, day 1, followed by 
Carboplatin AUC 6 IV over 30 min, day 1 
Every 21 days 
Prophylactic ciprofloxacin 500 mg twice daily, orally, on days 5-14 
Calculation of Carboplatin Dose 
The dose of Carboplatin during chemotherapy will be calculated using 
the following formula (Calvert equation): 
Carboplatin total dose in mg = AUC x (glomerular filtration rate  
[GFR] +25) 
NOTE: 
When calculating carboplatin dose, GFR should not 
exceed 125 mL/min. Thus, the maximum carboplatin dose 
for AUC of 6 will be 900 mg.  
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Calculated creatinine clearance (CrCl) will be used to estimate the 
GFR. The modified Cockcroft-Gault formula below should be used to 
calculate the creatinine clearance. 
140 – age (years) x actual weight (kg) / 72 x Serum creatinine 
(mg/dL) (for females, multiply the result by 0.85) 
The actual weight will be used for the calculation of Creatinine 
Clearance. 
5.1.3 
Regimen 2A (Cisplatin+5-FU) 
Cisplatin 100 mg/m2 IV over 1-2 hours on day 1, followed by 
5-FU 1000 mg/m2 /day as a continuous infusion x 4 days 
Every 21 days 
Prophylactic ciprofloxacin 500 mg twice daily, orally, on days 5-14 
Continue regimen until progression. Treatment may be discontinued if 
there is maximum response (i.e., no improvement in tumor 
measurements for 2 or more cycles) after cycle 6. 
If patients develop specific intolerable cisplatin-associated toxicities 
(see dose modifications, carboplatin substitution), such as 
neuropathy, renal impairment, ototoxicity, or nausea/vomiting, 
carboplatin at an AUC of 6 will be substituted for cisplatin. 
5.1.3.1 
Cisplatin will require aggressive hydration. Any preexisting 
dehydration should be corrected. 
Hydration Requirements 
Hydration guidelines may be modified at the discretion of 
the treating physician provided adequate pre and post 
cisplatin hydration is achieved and renal function remains 
adequate.  One suggested regimen consists of 
administering cisplatin in 500 cc to 1000 cc of IV fluids 
following adequate hydration and the establishment of 
adequate urinary output. It is suggested the pre-cisplatin 
hydration consist of NS at 500 cc/hr x 1 liter and post-
cisplatin hydration consist of 1/2 NS + 10 meq KCl/liter + 1 
gram magnesium sulfate/liter + 25 grams mannitol/liter at 
500 cc/hr for at least one hour, followed by additional 
hydration at the discretion of the investigator. 
5.1.3.2 
Days 2, 3, 4 
5-FU 1000 mg/m²/day for the following days for a total of 4 
consecutive days of treatment. 
The patient must be monitored during the next 24-48 hour 
post-cisplatin period for his ability to tolerate oral fluids. If 
an inadequate oral intake of fluids is observed the patient 
should be requested to return to the treatment facility for 
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5.1.3.3 
Antiemetics  
It is suggested that patients receive antiemetic therapy, 
acute and delayed, including dexamethasone, 5-HT3 
serotonin receptor antagonists and aprepitant, according to 
published ASCO guidelines (see Appendix VIII). However, 
the specifics of the regimen are at the discretion of the 
treating physician, provided adequate control is achieved. 
One potential regimen consists of 20 mg of oral or IV 
dexamethasone and a high dose of oral or IV 5-HT3 
antagonist (such as 2 mg oral or 10 mcg/kg IV granisetron, 
or 32 mg oral or IV ondansetron) on the day of cisplatin 
administration. Followed by additional anti-emetics 
consisting of oral dexamethasone and scheduled 5-HT3 
serotonin receptor antagonists on days 2-5. For example, 8 
mg orally, twice daily for days 2 and 3, and then 4 mg 
orally, twice daily for days 4 and 5, especially if aprepitant 
is not given. Aprepitant should be used with caution when 
combined with docetaxel due to the possibility of a drug 
interaction with docetaxel via CYP3A4 pathway. On the 
day of chemotherapy administration, the dose of 
dexamethasone must be reduced by 50%, if aprepitant is 
given. 
5.1.4 
Regimen 2A carbo (Carboplatin/5-FU) 
Carboplatin AUC 6 IV over 30 min, day 1 
5-FU 1000 mg/m2 /day as a continuous infusion x 4 days 
Every 21 days 
Prophylactic ciprofloxacin 500 mg twice daily, orally, on days 5-14 
Calculation of Carboplatin Dose 
The dose of Carboplatin during chemotherapy will be calculated using 
the following formula (Calvert equation): 
Carboplatin total dose in mg = AUC x (glomerular filtration rate  
[GFR] +25) 
NOTE: 
When calculating carboplatin dose, GFR should not 
exceed 125 mL/min. Thus, the maximum carboplatin dose 
for AUC of 6 will be 900 mg.  
Calculated creatinine clearance (CrCl) will be used to estimate the 
GFR. The modified Cockcroft-Gault formula below should be used to 
calculate the creatinine clearance. 
140 – age (years) x actual weight (kg) / 72 x Serum creatinine 
(mg/dL) (for females, multiply the result by 0.85) 
The actual weight will be used for the calculation of Creatinine 
Clearance. 
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5.2 
Treatment Arm B (with bevacizumab) 
Investigators may choose one of 4 regimens (regimen 1, 1 carbo, 2, or 2 
carbo) at registration and prior to randomization. 
Same chemotherapy regimens as in Arm A (see 5.1) plus bevacizumab, prior to 
chemotherapy, i.e.: 
Regimen 1B: Bevacizumab + Docetaxel + Cisplatin 
Regimen 1B carbo: Bevacizumab + Docetaxel + Carboplatin 
Regimen 2B: Bevacizumab + Cisplatin + 5-FU 
Regimen 2B carbo: Bevacizumab + Carboplatin + 5-FU 
5.2.1 
Bevacizumab Administration (Arm B) 
Each cycle is 3 weeks (21 days). 
For all patients randomized to Arm B: 
• 
The chemotherapy is identical to that of Arm A (see Section 5.1). 
The investigator is required to choose the chemotherapy regimen 
for the patient (1, 1 carbo, 2, or 2 carbo) prior to randomization.  
• 
Bevacizumab 15 mg/kg IV, day 1 of each cycle 
• 
Bevacizumab will be administered with chemotherapy until 
disease progression. Chemotherapy may be discontinued if there 
is maximum response after 6 cycles. Bevacizumab administration 
will continue until disease progression. 
NOTE: 
Whenever bevacizumab is given with chemotherapy, it will 
be given prior to chemotherapy. 
NOTE: 
The subject’s actual weight at screening should be used to 
calculate the bevacizumab dose.  If a subject’s weight 
changes by ³ 10% during the course of the study, the 
bevacizumab dose should be recalculated (see Section 8 
for preparation guidelines). 
NOTE: 
Prior to each treatment, the patient should be carefully 
assessed with special attention to blood pressure, 
proteinuria, bleeding and cardiovascular events.   
NOTE: 
Decisions for retreatment or dose modification/interruption 
should follow the dose modification guidelines in Section 
5.5. 
5.2.1.1 
Rate of Infusion 
The initial bevacizumab dose should be delivered over 90 
minutes as a continuous IV infusion prior to all 
chemotherapy infusions. If the first infusion is tolerated 
without infusion-associated adverse events (fever and/or 
chills), the second infusion may be delivered over 60 
minutes. If the 60-minute infusion is well tolerated, all 
subsequent infusions may be delivered over 30 minutes. 
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If a patient experiences bevacizumab infusion-associated 
adverse events, patient may receive premedication 
(acetaminophen, diphenhydramine, steroids or other 
medications given for symptom control) at the 
investigators’ discretion, prior to the next bevacizumab 
infusion. If premedication is required, the infusion time may 
not be decreased for the subsequent infusion.  However, if 
the next infusion is well tolerated with premedication, the 
subsequent infusion time may then be decreased by 30 
minutes per infusion to a minimum infusion time of 30 
minutes, as long as the patient continues to receive the 
same premedication. 
If a premedicated patient experiences infusion-associated 
adverse events with the 60-minute infusion, all subsequent 
doses should be given over 90 minutes. Similarly, if a 
premedicated patient experiences infusion-associated 
adverse events with the 30-minute infusion, all subsequent 
doses should be given over 60 minutes. 
A rate-regulating device should be used for all 
bevacizumab infusions. When the bevacizumab IV bag is 
empty, 50 mL of 0.9% sodium chloride injection, USP, 
should be added to the IV bag or an additional bag should 
be hung. An alternative method of flushing the infusion line 
would be to replace the empty bevacizumab infusion bag 
with a 50 mL bag of 0.9% sodium chloride injection and 
infuse a volume equal to that of the tubing to ensure 
complete delivery of the bevacizumab. The infusion should 
be continued for a volume equal to that of the tubing to 
ensure complete delivery of the bevacizumab. 
5.2.1.2 
Anaphylaxis Precautions 
Anaphylaxis precautions should be observed during 
bevacizumab administration.   
The patient’s blood pressure and heart rate should be 
monitored every 15 minutes during the infusion.   
Emergency agents including oxygen, oral and 
endotracheal airways, intubation equipment, epinephrine, 
antihistamines and corticosteroids should be available.   
In the event of a suspected anaphylactic reaction during 
bevacizumab infusion, stop the bevacizumab infusion and 
apply a tourniquet proximal to the injection site, if possible, 
to slow systemic absorption of bevacizumab.  Administer 
antihistamines, epinephrine, or other medications at the 
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5.2.1.3 
Bevacizumab Infiltration 
Should infiltration of the bevacizumab infusion occur, the 
following steps are to be taken: 
• 
Discontinue the IV. 
• 
If a significant volume of the bevacizumab infusion 
remains, restart the IV and complete the infusion. 
• 
Treat the infiltration according to institutional guidelines 
for infiltration of a noncaustic agent. 
5.2.1.4 
Hypertension 
Hypertension is a known and potentially serious adverse 
event associated with bevacizumab treatment. Patients 
should have their BP monitored closely during the first 
cycle of therapy and prior to each infusion of bevacizumab.  
Hypertensive mediation should be initiated or increased 
per routine practice. Bevacizumab treatment modifications 
due to hypertension should follow the instructions in 
Section 5.5.3. 
5.2.1.5 
Wound complications and surgery 
The appropriate interval from discontinuation of 
bevacizumab to subsequent elective surgery required to 
reduce the risk of impaired wound healing has not been 
determined.  Decision on such an interval should take into 
consideration the half-life of bevacizumab.  It is generally 
recommended that bevacizumab should be discontinued at 
least 4 weeks prior to major elective surgery.  In addition, 
bevacizumab should not be restarted until at least 4 weeks 
after major surgery provided that the wound has 
adequately healed. 
NOTE: 
If, for any reason, patient is off bevacizumab for 
≥ 4 weeks, Study Chair or Study Co-Chair must 
be contacted, and the case discussed, before 
patient may resume protocol treatment.  
5.2.1.6 
Supportive Care Guidelines 
Patients may continue all medications used as part of 
supportive care unless otherwise stated in Section 5.8. 
IV fluids, transfusions of blood and blood products, 
antibiotics, anti-emetics, etc., should be administered if 
appropriate. The reason(s) for treatment, dosage, and the 
dates of treatment should be recorded on the flow sheets. 
5.3 
Adverse Event Reporting Requirements 
5.3.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
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using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E1305 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.3.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
When a study arm includes both investigational and commercial 
agents, the following rules apply. 
• 
Concurrent administration: When an investigational agent(s) is 
used in combination with a commercial agent(s), the combination 
is considered to be investigational and expedited reporting of 
adverse events would follow the guidelines for investigational 
agents. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0 will be utilized until September 30, 2011 
for AE reporting. CTCAE version 4.0 will be utilized beginning October 
1, 2011. All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
Step 2: Grade the event using the NCI CTCAE version 4.0. 
Step 3: Determine whether the adverse event is related to the protocol 
therapy (investigational or commercial). Attribution categories are as 
follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
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Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is NOT listed in: 
• 
Arm A – the drug package insert or protocol 
• 
Arm B – the current NCI Specific Protocol Exceptions to 
Expedited Reporting (SPEER) for Bevacizumab or package 
insert/protocol for the commercial agents 
NOTE: 
The NCI SPEER for Bevacizumab is included in Section 
5.4 of the protocol. 
• 
FOR THIS PROTOCOL, events listed in the SPEER for 
Bevacizumab should be considered EXPECTED if the grade 
being reported is the same or lower than the grade noted in the 
parentheses next to the AE in the SPEER.  Events listed in the 
SPEER column should be considered UNEXPECTED if the grade 
being reported exceeds the grade noted in parentheses next to 
the AE in the SPEER. 
• 
For Arm B, if the event being reported is listed in EITHER the 
SPEER for Bevacizumab or the package insert/protocol for the 
commercial agents, then it is considered ‘expected’ for CTEP-
AERS adverse event reporting purposes, regardless of the grade. 
• 
The SPEER is presented in the last column of the CAEPR and 
identified with bold and italicized text. 
Step 5: 
Review the ”Additional instructions, requirements, and 
exceptions for protocol E1305” table in Section 5.3.6 and footnote b in 
Section 5.3.7 for protocol and/or ECOG-ACRIN specific requirements 
for expedited reporting of specific adverse events that require special 
monitoring.   
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. 
5.3.3 
Reporting Methods 
Arm A and B – This study requires that expedited adverse event 
reporting use the CTEP’s Adverse Event Reporting System (CTEP-
AERS). CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov. A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) and 
• 
the FDA (800-332-1088) for patient on Arm A and 
• 
the NCI (301-897-7497) for patients on Arm B 
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An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Any supporting or follow up documentation must be faxed to ECOG-
ACRIN (617-632-2990), Attention: AE.  In addition, supporting or 
follow up documentation must be faxed to  
• 
the FDA (800-332-0178) for patients on Arm A 
• 
the NCI (301-230-0159) for patients on Arm B 
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.3.4 
When to Report an Event in an Expedited Manner 
Some adverse events require 24-hour notification (refer to Sections 
5.3.6 and 5.3.7). Please complete a 24-Hour Notification Report via 
the CTEP-AERS website (http://ctep.cancer.gov) within 24 hours of 
learning of the event. The full CTEP-AERS report must be completed 
and submitted via CTEP-AERS within 5 calendar days. 
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (617-632-3610), and for Arm B, to NCI (301-
897-7497). Once the system is restored, a 24-hour Notification Report 
must be entered into the CTEP-AERS system by the original 
submitter of the report at the site. 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Sections 5.3.6 
and 5.3.7. 
NOTE: 
Adverse events that meet the reporting requirements in 
Sections 5.3.6 or 5.3.7 and occur within 30 days of the last 
dose of protocol treatment must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
For any adverse events that occur more than 30 days after 
the last dose of treatment, only those that have an 
attribution of possibly, probably, or definitely AND meet the 
reporting requirements in Sections 5.3.6 or 5.3.7 must be 
reported on an expedited adverse event report form (using 
CTEP-AERS). 
5.3.5 
Other Recipients of Adverse Event Reports 
DCTD, NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to the NCI and 
ECOG-ACRIN. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
 

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5.3.6 
Expedited Reporting for Investigational Agents (Arm B) 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-
AERS Expedited Reporting Requirements for Adverse Events 
That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent (Bevacizumab) in this Study (Arm B) OR Within 30 Days of 
the Last Dose of Any Protocol Treatment. 
Attribution 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
Unexpected Expected 
Unexpected 
Expected 
Unexpected Expected 
with 
Hospital-
ization 
without 
Hospital-
ization 
with 
Hospital
-ization 
Without 
Hospital
-ization 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour;  
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the 
last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
Please see additional information below under section entitled “Additional instructions, requirements, and 
exceptions for protocol E1305” 
March 2005 
NOTE: 
All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines: 
Ø 24 Hours; 5 calendar days – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
Ø 10 calendar days – A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization* (or prolongation of existing hospitalization) must be 
reported regardless of attribution and designation as expected or unexpected 
with the exception of any events identified as protocol-specific expedited adverse 
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• 
Any event that results in persistent or significant disability/incapacity, 
congenital anomaly, or birth defect must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
*Hospitalizations are defined as lasting 24 hours or longer and these events must 
be reported via CTEP-AERS. 
Additional instructions, requirements and exceptions for protocol E1305 
1. Additional Instructions: 
Ø With respect to determining the specific day by which the event must be reported, 
the day the reporter learns of the adverse event constitutes “Day 0” 
Ø For grade 2 and 3 unexpected events, CTEP-AERS reporting is only required if the 
event is related to the investigational agent(s); it is not required if the event is related 
only to the commercial agent(s) included in the protocol treatment. 
NOTE: 
For grade 3 unexpected events with hospitalization lasting ³ 24 hours (or 
prolonged hospitalization), a CTEP-AERS report is required even if the 
event is unrelated to the investigational agent(s). 
Ø For instructions on how to specifically report events that result in persistent or 
significant disability/incapacity, congenital anomaly, or birth defect events via CTEP-
AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-
7497.  This will need to be discussed on a case-by-case basis.. 
2. ECOG-ACRIN and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG-ACRIN specific expedited reporting requirements: 
Ø 
Hospitalizations: Any grade 1 or 2 adverse event which precipitates a 
hospitalization lasting ≥ 24 hours (or prolongs hospitalization) must be reported via 
CTEP-AERS within 10 calendar days of learning of the event regardless of the 
attribution and designation as expected or unexpected.   
Protocol specific expedited reporting requirements: 
Ø 
RPLS or PRES: All occurrences of Reversible Posterior Leukoencephalopathy 
Syndrome (RPLS) or Posterior Reversible Encephalopathy Syndrome (PRES) 
and associate clinical presentations [please report under Neurology-Other 
(Leukoencephalopathy syndrome)] must be submitted within 10 calendar days of 
learning of the event, regardless of attribution. 
Ø 
Hemorrhage:  Any grade 3-5 hemorrhage event, requires a CTEP-AERS report 
within 10 calendar days of learning of the event, regardless of the attribution. 
NOTE: 
If it is a grade 4-5 unexpected event with an attribution of possible, 
probable, or definite, the investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
Ø 
Arterial Thromboembolic Events:  Any grade 3-5 arterial thromboembolic event 
(i.e. cardiac ischemia, CNS ischemia, peripheral or visceral arterial ischemia) 
requires a CTEP-AERS report within 10 calendar days of learning of the event, 
regardless of the attribution. 
NOTE: 
If it is a grade 4-5 unexpected event with an attribution of possible, 
probable, or definite, the investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete 
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Ø 
Fistula:  Any grade 3-5 fistula requires a CTEP-AERS report within 10 calendar 
days of learning of the event, regardless of the attribution. 
NOTE: 
NOTE: 
If it is a grade 4-5 unexpected event with an attribution of 
possible, probable, or definite, the investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
3. Protocol specific expedited reporting exceptions: 
For study arm B, the adverse events listed below do not require expedited reporting via 
CTEP-AERS: 
Grade 4 expected myelosuppression (unless it results in a hospitalization, in which case, 
a CTEP-AERS report is required). 
 
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5.3.7 
Expedited reporting for commercial agents (Arm A)  
Commercial reporting requirements are provided below. The commercial agents used in arm A of this study 
are Docetaxel, Cisplatin, 5-FU, and Carboplatin. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents only – Arm A  
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and Protocol-
Specific Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special requirements. 
Unrelated or 
Unlikely 
 
 
7 calendar days 
7 calendar days 
Possible,  
Probable,  
Definite 
7 calendar days 
 
7 calendar days 
7 calendar days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any death that occurs > 30 days after the last dose 
of treatment and is attributed possibly, probably, or definitely to the treatment must be reported within 7 calendar days of learning of the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited reporting for this trial: 
Serious Events: 
Any event following treatment that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects 
must be reported via CTEP-AERS within 7 calendar days of learning of the event.  For instructions on how to specifically report 
these events via CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-7497.  This will need to be 
discussed on a case-by-case basis. 
RPLS or PRES: 
All occurrences of Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or Posterior Reversible Encephalopathy 
Syndrome (PRES) and associate clinical presentations [please report under Neurology-Other (Leukoencephalopathy syndrome)] 
must be submitted within 10 calendar days of learning of the event, regardless of attribution.  
Hemorrhage: 
Any grade 3-5 hemorrhage event, requires a CTEP-AERS report within 7 calendar days of learning of the event, regardless of the 
attribution. 
Arterial Thromboembolic Events: 
Any grade 3-5 arterial thromboembolic event (i.e. cardiac ischemia, CNS ischemia, peripheral or visceral arterial 
ischemia) requires a CTEP-AERS report within 7 calendar days of learning of the event, regardless of the attribution. 
Fistula: 
Any grade 3-5 fistula requires a CTEP-AERS report within 7 calendar days of learning of the event, regardless of the attribution. 
Myelosuppression: 
Grade 4 or higher myelosuppression resulting in hospitalization requires a CTEP-AERS report within 7 calendar days of learning of 
the event. 
 
 
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5.3.8 
Reporting Secondary Primary Cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol).  
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) treatment 
related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
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pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
 

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8/14, 10/16 
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5.5 
Dose Modifications 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
The CTCAE version 4.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. 
IF A PATIENT EXPERIENCES SEVERAL TOXICITIES AND THERE ARE 
CONFLICTING RECOMMENDATIONS, PLEASE FOLLOW THE MOST 
CONSERVATIVE DOSE ADJUSTMENT RECOMMENDED (DOSE REDUCTION 
APPROPRIATE TO THE MOST SEVERE TOXICITY). 
NOTE THAT THE DOSES WHICH HAVE BEEN REDUCED FOR TOXICITY 
MUST NOT BE RE-ESCALATED. 
If one of the two chemotherapy drugs, in any of the 4 regimens, are permanently 
discontinued due to toxicities that can only be attributed to this drug, the second 
chemotherapy drug will be continued and the patient remain on study after 
discussing with the study chair or co-chair. 
Patients who do not receive any scheduled chemotherapy during a treatment 
delay for > 3 weeks due to ongoing toxicities will be removed from study 
treatment. 
5.5.1 
Cisplatin + Docetaxel (Regimen 1A and Regimen 1B) 
5.5.1.1 
Docetaxel Dose Reduction Levels 
Docetaxel dose level 
Dose in mg/m2 
Original Dose  
75 
Level - 1 
56 
Level - 2 
42 
5.5.1.2 
Cisplatin Dose Reduction Levels 
Cisplatin dose level 
Dose in mg/m2 
Original Dose  
75 
Level - 1 
56 
Level - 2 
42 
NOTE: 
Dose may not be re-escalated after reduction 
for toxicity. If > 2 dose reductions are required 
for any agent due to toxicity, treatment with that 
agent will be discontinued. 
5.5.1.3 
Hematologic Toxicity (Docetaxel) 
Day 1 cycle dose adjustments (hematologic toxicity): 
ANC must be ≥ 1,500/mm³ and platelet count must be  
≥ 100,000/mm3 on day 1 of each cycle. Treatment can be 
delayed for up to 3 weeks until the day 1 ANC is  
≥ 1,500/mm3 and the platelet count is ≥ 100,000/mm3. 
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(Reduce doses only for febrile neutropenia or if ANC is  
< 500/mm3 for > 5 days or if platelet nadir is  
< 25,000/mm3.) 
Please see table below: 
Table 1. Dose Modifications on day 1 based on nadir 
during previous cycle 
 
Cisplatin 
Docetaxel 
1st episode* 
No adjustment 
Dose reduce by 1 level 
2nd episode*  
No adjustment 
Dose reduce by 1 level 
3rd episode 
Discontinue 
protocol therapy 
Discontinue 
 protocol therapy 
Anemia 
No adjustment 
No adjustment 
* Episodes = 1) Febrile Neutropenia or 2) ANC< 500/mm3 x > 5 
days or 3) Platelet Nadir < 25,000/mm3 
Treatment should be delayed for up to 3 weeks until the 
day 1 ANC is at least 1,500/mm3 and the platelet count is 
at least 100,000/mm3. However, if the counts have not 
recovered in 3 weeks, the patient’s protocol treatment will 
be discontinued. The patient will still be followed for toxicity 
and response. Patient and investigators need to be 
attentive to the possibility of fever and infection so that 
these complications can be promptly and appropriately 
managed. 
If chemotherapy must be withheld due to hematologic 
toxicity, CBC and platelet counts should be obtained at 
least twice a week until the counts reach the lower limits 
for treatment.  The treatment schedule will then proceed in 
the usual schedule. 
No dose reductions will be made for anemia.  Patients 
should be supported per the treating physician’s discretion. 
The use of growth factor support for anemia will be 
allowed, as will blood transfusions as indicated. 
Dose reductions, once initiated, are permanent for all 
future cycles.  If both febrile neutropenia and 
thrombocytopenia of < 25,000/mm3 occur, the dose 
reduction will be to the lower dose specified. 
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.  

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5.5.1.4 
Gastrointestinal Toxicities (Cisplatin and Docetaxel) 
5.5.1.4.1 
Nausea/Vomiting (Cisplatin, Docetaxel) 
Nausea and/or vomiting should be 
controlled with antiemetics. If grade 3 
nausea/vomiting occurs in spite of 
maximum antiemetics (steroids, 5HT3 
antagonist, and aprepitant or similar agent if 
available), the dose of cisplatin should be 
reduced by 1 dose level for the next course. 
Doses of docetaxel may be reduced by 1 
dose level in subsequent cycles, if needed. 
5.5.1.4.2 
Diarrhea (Docetaxel) 
If diarrhea is grade ≤ 2 and lasts less than 2 
weeks, no dose modification will be made. 
If diarrhea is observed, supportive treatment 
can be given and prophylactic treatment 
with loperamide is recommended for next 
cycles. In the case of severe diarrhea, 
octreotide is recommended. 
If, despite these measures, grade 3 diarrhea 
still occurs, or grade 2 diarrhea persists > 2 
weeks, the docetaxel dose will be reduced 
by 1 dose level. 
If diarrhea is grade 4 then discontinue 
protocol treatment. 
5.5.1.4.3 
Mucositis Oral (Docetaxel) 
If mucositis is present on day 1 of any cycle, 
treatment should be withheld until mucositis 
has resolved to grade 0.   
If Grade 3 mucositis occurs at any time, the 
dose of docetaxel should be reduced by 1 
dose level and docetaxel resumed when the 
mucositis has resolved to grade 0. This is a 
permanent dose reduction. 
• 
In case of grade 4 mucositis, the patient 
has to discontinue the treatment. 
If the mucositis has not cleared in 3 weeks, 
the patient’s protocol treatment will be 
discontinued.  
5.5.1.5 
Nephrotoxicity (Cisplatin) 
Measurement of serum creatinine is required before each 
cycle of drug. Modify the Cisplatin dose using the following 
parameters for calculated creatinine clearance determined 
in the well-hydrated patient using the 
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Cockcroft-Gault formula. The actual weight will be used for 
the calculation of creatinine clearance.   
CrCl(males) = (140-age) x weight(kg)/(creatinine x 72)  
CrCl(females) = CrCl(males) x 0.85 
If the clearance of creatinine (CCl) is ≥ 60 ml/min: the full 
dose will be given and CCl will be repeated before each 
cycle. 
• 
If the CCl is between 50 and 59 ml/min : the dose 
of cisplatin will be reduced by 2 dose levels at 
subsequent cycles (doses which have been reduced 
for toxicity must not be reescalated). 
NOTE: 
In a second instance of CCl between 50 and 
59 ml/min (when the cisplatin dose has 
already been reduced by 2 dose levels) 
carboplatin will be used instead of cisplatin 
(see carboplatin substitution Section 5.5.6). 
• 
If CCl is < 50 ml/min (for ≥ 1 week): 
CARBOPLATIN WILL BE USED INSTEAD OF 
CISPLATIN. 
If the creatinine clearance is between 50-59 ml/min, 
docetaxel should be continued at the dose dictated by 
myelosuppression and should be given on schedule. If the 
creatinine clearance is < 50 ml/min, withhold any therapy 
until creatinine clearance improves. If creatinine clearance 
remains < 50 ml/min for ≥ 1 week, switch to carboplatin 
(see carboplatin substitution Section 5.5.6) and continue 
docetaxel at the dose dictated by myelosuppression. 
If serum creatinine increased at any time to > 4 mg/dL, 
carboplatin will be used instead of cisplatin (see 
carboplatin substitution Section 5.5.6). 
5.5.1.6 
Neurologic Toxicity (Cisplatin, Docetaxel) 
Cisplatin and docetaxel doses should be modified as 
follows for neurologic toxicity. The day 1 value should be 
used in determining dose. Dose modifications made for 
neurotoxicity are permanent reductions. 
Grade of 
toxicity 
Cisplatin/docetaxel doses to give 
0 
100% 
1 
100% 
2 
Hold treatment until patient recovers to 
grade 0 or 1 toxicity, then resume treatment 
but reduced by 1 dose level for both drugs.  
If persistent grade 2 for > 1 week, may use 
carboplatin instead of cisplatin (see 
carboplatin substitution Section 5.5.6) 
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3 or worse 
Discontinue treatment 
 
5.5.1.6.1 
Auditory Toxicity (Cisplatin) 
Cisplatin is well known to cause high-
frequency hearing loss. Continued use of 
the drug does not always result in hearing 
loss, although it may do so. If transient 
grade 2 hearing loss is noted, the patient 
should 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.  
If grade 2 ototoxicity is persistent or 
intolerable, patients will be treated with 
carboplatin, instead of cisplatin (see 
carboplatin substitution Section 5.5.6). 
Severe hearing loss (grades 3 and 4) is an 
indication to discontinue cisplatin. 
5.5.1.7 
Hepatic Toxicity (Docetaxel) 
The day 1 value should be used in determining dose. 
Both AST and ALT should be drawn.  The more abnormal 
of the two values (AST or ALT) should be used in 
determining the dose. 
Patients who develop abnormal liver function tests for any 
reason while on the study will have the following dose 
reductions: 
Docetaxel Dose Modifications for Abnormal Liver Function 
 
AST or ALT: 
ALK 
PHOS: 
£ ULN 
>1x but £1.5x  
>1.5x but £5x  
>5x ULN 
≤ ULN 
Full Dose 
Full Dose 
Full Dose 
Hold* 
>1x but  
£ 2.5x  
Full Dose 
Full Dose 
Reduce Dose  
by 1 dose level 
Hold* 
>2.5x but 
£ 5x  
Full Dose 
Reduce Dose  
by 1 dose level 
Hold* 
Hold* 
>5x ULN 
Hold* 
Hold* 
Hold* 
Hold* 
* Hold until recovered, maximum 14 days, then re-treat at a reduced dose by 
1 dose level. “Recovered” is defined as meeting the study baseline 
eligibility criteria (see Table in 3.11). 
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If docetaxel cannot be administered for >14 days, it 
will be permanently discontinued and cisplatin will be 
continued alone. 
Bilirubin: Docetaxel should not be administered to 
patients with serum total bilirubin >ULN.  If serum total 
bilirubin is >ULN on treatment day, hold docetaxel until 
serum total bilirubin is £ ULN (maximum 14 days), then re-
treat at a reduced dose by 1 dose level. 
5.5.1.8 
Hypersensitivity Reactions (Docetaxel) 
See Section 5.8.4 for management. Patients who develop 
grade 4 (life- threatening) hypersensitivity reaction will be 
removed from the study.   
5.5.1.9 
Cutaneous Reactions (Docetaxel) 
Grade 0, 1 and 2:  No change 
Grade 3:  Delay all chemotherapy until ≤ grade 1 and 
retreat with a dose reduction of docetaxel by 1 
dose level. If no recovery to ≤ grade 1 within 2 
weeks delay, patient will go off protocol therapy. 
Grade 4:  The patient will go off study immediately. 
Nail changes will not result in dose-modification. 
5.5.1.9.1 
Fluid Retention (Docetaxel) 
No dose reduction is planned for fluid 
retention.  
Fluid retention should be managed as 
outlined in Section 5.8.2. Further therapy 
following fluid retention should be 
customized depending upon the clinical 
situation. 
5.5.1.9.2 
Other Toxicities 
For any clinically significant grade 3 or 4 
toxicity not mentioned above, the treatment 
should be withheld until the patient recovers 
completely or to grade 1. The treatment 
should then be reduced by 1 dose level 
(permanent dose reduction). This dose 
reduction will be discussed between 
investigator and study chair. For grade 1 
and 2 toxicities, no dose reduction should 
be made. 
For carboplatin substitution (for neuropathy, 
nephrotoxicity, ototoxicity, or 
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5.5.2 
Carboplatin + Docetaxel (Regimen 1A carbo and Regimen 1B carbo) 
Docetaxel Dose Reduction Levels 
Docetaxel dose level 
Dose in mg/m2 
Original Dose  
75 
Level - 1 
56 
Level - 2 
42 
Carboplatin Dose Reduction Levels 
Carboplatin dose level 
Dose in AUC 
Original Dose  
6 
Level - 1 
4.5 
Level - 2 
3 
NOTE: 
Dose may not be re-escalated after reduction for toxicity.  If 
> 2 dose reductions are required for any agent due to 
toxicity, treatment with that agent will be discontinued. 
5.5.2.1 
Dose Modifications for Carboplatin 
NOTE: 
Dose modifications for docetaxel will follow the 
docetaxel specific instructions in Section 5.5.1 
1) Carboplatin will be administered if platelets are  
≥ 100,000 cells/mm3 above and ANC is 1500  
≥ cells/mm3. Treatment will be delayed up to 3 weeks 
until the above criteria are met. 
2) 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, carboplatin dose will be reduced 
to AUC of 4.5 in all subsequent administrations. A 
second dose reduction to AUC of 3 is allowed. 
3) Patients developing grade 3 or 4 neuropathy will have 
carboplatin discontinued and will be taken off study 
treatment. 
Dose Modifications for Carboplatin and Docetaxel on 
day 1 based on nadir during previous cycle 
 
Carboplatin 
Docetaxel 
1st episode* 
Dose reduce by 1 level 
Dose reduce by 1 level 
2nd episode*  
Dose reduce by 1 level 
Dose reduce by 1 level 
3rd episode 
Discontinue protocol 
therapy 
Discontinue protocol 
therapy 
Anemia 
No adjustment 
No adjustment 
* Episodes = 1) Febrile Neutropenia or 2) ANC< 500/mm3 x > 5 days 
or 3) Platelet Nadir < 25,000/mm3 
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Treatment should be delayed for up to 3 weeks until the 
day 1 ANC is at least 1,500/mm3 and the platelet count is 
at least 100,000/mm3. However, if the counts have not 
recovered in 3 weeks, the patient’s protocol treatment will 
be discontinued. The patient will still be followed for toxicity 
and response. Patient and investigators need to be 
attentive to the possibility of fever and infection so that 
these complications can be promptly and appropriately 
managed. 
If chemotherapy must be withheld due to hematologic 
toxicity, CBC and platelet counts should be obtained at 
least twice a week until the counts reach the lower limits 
for treatment. The treatment schedule will then proceed in 
the usual schedule. 
No dose reductions will be made for anemia. Patients 
should be supported per the treating physician’s discretion. 
The use of growth factor support for anemia will be 
allowed, as will blood transfusions as indicated. 
Dose reductions, once initiated, are permanent for all 
future cycles.  If both febrile neutropenia and 
thrombocytopenia of < 25,000/mm3 occur, the dose 
reduction will be to the lower dose specified. 
 
5.5.3 
Cisplatin + 5-FU (Regimen 2A and Regimen 2B) 
Cisplatin dose level 
Dose in mg/m2 
Original Dose  
100 
Level   -1 
75 
Level    -2 
56 
 
5-FU dose level 
Dose in mg/m2/day  
(duration of infusion is 4 days) 
Original Dose  
1000 
Level   -1 
750 
Level    -2 
560 
NOTE: 
Dose may not be re-escalated after reduction for toxicity. If 
> 2 dose reductions are required for any agent due to 
toxicity, treatment with that agent will be discontinued. 
5.5.3.1 
Hematologic Toxicities (Cisplatin + 5-FU) 
If the neutrophil count is < 1500/mm3 and/or platelet count 
is < 100,000/mm3, on day 21, the cycle will be delayed by 
maximum 3 weeks. Blood counts should be repeated twice 
a week until recovery. 
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If no recovery occurs after 3 weeks delay, the patient will 
go off study. 
In case of febrile neutropenia the following is 
recommended: 
Adverse event 
 
• Febrile neutropenia 
 
1. 
The first episode of febrile 
neutropenia will result in 
reduction by 1 dose level of both 
the cisplatin and 5-FU doses 
(while maintaining the duration 
of 5-FU infusion of 4 days).* 
 
2. 
If there is a second episode, a 
second dose reduction by 1 
dose level for both drugs will be 
applied. 
 
3. 
If there is a third episode, the 
patient will go off study 
* The use of growth factor support for anemia will be allowed, as 
will blood transfusions as indicated. 
5.5.3.2 
Diarrhea (5-FU) 
If diarrhea is observed, supportive treatment can be given 
and prophylactic treatment with loperamide is 
recommended for next cycles.  
If despite these measures grade 3 diarrhea still occurs, the 
dose of 5-FU will be reduced by 1 dose level in the next 
cycle. In case of grade 4 diarrhea, the patient will go off 
study treatment. 
5.5.3.3 
Mucositis Oral (5-FU) 
In case of grade 3 mucositis lasting more than 48 hours, 5-
FU dose will be reduced by 1 dose level. 
• 
In case of grade 4 mucositis, the patient will go off 
study treatment. 
5.5.3.4 
Nephrotoxicity (Cisplatin) 
Measurement of serum creatinine is required before each 
cycle of drug. Modify the Cisplatin dose using the following 
parameters 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.   
CrCl(males) = (140-age) x weight(kg)/(creatinine x 72)  
CrCl(females)= CrCl(males) x 0.85 
If the clearance of creatinine (CCl) is >= 60 ml/min: the full 
dose will be given and CCl will be repeated before each 
cycle. 
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• 
If the CCl is between 50 and 59 ml/min : the dose of 
cisplatin will be reduced by 2 dose levels at 
subsequent cycles (doses which have been reduced 
for toxicity must not be reescalated). 
NOTE: 
In a second instance of CCl between 50 and 
59 ml/min (when the cisplatin dose has 
already been reduced by 2 dose levels) 
carboplatin will be used instead of cisplatin 
(see carboplatin substitution Section 5.5.6). 
• 
If CCl is < 50 ml/min (for ≥ 1 week): CARBOPLATIN 
WILL BE USED INSTEAD OF CISPLATIN. 
If the creatinine clearance is between 50-59 ml/min, 5-FU 
should be given on schedule. If the creatinine clearance is 
< 50 ml/min, withhold any therapy until creatinine 
clearance improves. If creatinine clearance remains < 50 
ml/min for ≥ 1 week, switch to carboplatin (see carboplatin 
substitution Section 5.5.6) and continue 5-FU. 
If serum creatinine increased at any time to >4 mg/dL, 
carboplatin will be used instead of cisplatin (see 
carboplatin substitution Section 5.5.6). 
5.5.3.5 
Neurologic Toxicity (Cisplatin) 
Cisplatin doses should be modified as follows for 
neurologic toxicity. The day 1 value should be used in 
determining dose. Dose modifications made for 
neurotoxicity are permanent reductions. 
Grade of toxicity 
Cisplatin doses to give 
0 
100% 
1 
100% 
2 
Hold treatment until patient recovers 
to grade 0 or 1 toxicity, then resume 
treatment with a 1 dose level dose 
reduction.  
If persistent grade 2 for > 1 week, may 
use carboplatin instead of cisplatin 
(see carboplatin substitution Section 
5.5.6) 
3 or worse 
Discontinue treatment 
 
5.5.3.5.1 
Auditory Toxicity (Cisplatin) 
Cisplatin is well known to cause high-
frequency hearing loss. Continued use of 
the drug does not always result in hearing 
loss, although it may do so. If transient 
grade 2 hearing loss is noted, patient should 
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be presented with a discussion of the 
relative risk of hearing loss versus the 
potential benefit of continuing cisplatin 
therapy, and a decision made on the 
continuation of cisplatin.  
If grade 2 ototoxicity is persistent or 
intolerable, patients will be treated with 
carboplatin, instead of cisplatin (see 
carboplatin substitution Section 5.5.6). 
Severe hearing loss (grades 3 and 4) is an 
indication to discontinue the drug. 
5.5.3.6 
Nausea and/or Vomiting (Cisplatin/5-FU)  
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 1 dose level for the next course. Doses of 5-FU may be 
reduced by 1 dose level in subsequent cycles if needed.  
5.5.3.7 
Other Toxic Effects 
For any clinically significant grade 3 or 4 toxicity not 
mentioned above, the treatment should be withheld until 
the patient recovers completely or to grade 1. The 
treatment should then be resumed 1 dose level lower 
(permanent dose reduction). This dose reduction will be 
discussed between investigator and study co-chair. For 
grade 1 and 2 toxicities, no dose reduction should be 
made. 
For carboplatin substitution (for neuropathy, nephrotoxicity, 
ototoxicity, or nausea/vomiting) see Section 5.5.6. 
5.5.4 
Carboplatin + 5-FU (Regimen 2A carbo and 2B carbo) 
Carboplatin Dose Reduction Levels 
Carboplatin dose 
level 
Dose in AUC 
Original Dose  
6 
Level - 1 
4.5 
Level - 2 
3 
5-FU Dose reduction Levels 
5-FU dose level 
Dose in mg/m2/day 
(duration of infusion is 4 days) 
Original Dose  
1000 
Level - 1 
750 
Level - 2 
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NOTE: 
Dose may not be re-escalated after reduction for toxicity. If 
> 2 dose reductions are required for any agent due to 
toxicity, treatment with that agent will be discontinued 
NOTE: 
Dose may not be re-escalated after reduction for toxicity. If 
> 2 dose reductions are required for any agent due to 
toxicity, treatment with that agent will be discontinued. 
5.5.4.1 
Dose Modifications for Carboplatin 
NOTE: 
Dose modifications for 5-FU will follow the 5-FU 
specific instructions in Section 5.5.3. 
1) Carboplatin will be administered if platelets are  
≥ 100,000 cells/mm3 above and ANC is  
1500 ≥ cells/mm3. Treatment will be delayed up to 3 
weeks until the above criteria are met. 
2) 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, carboplatin dose will be reduced 
to AUC of 4.5 in all subsequent administrations. A 
second dose reduction to AUC of 3 is allowed. 
3) Patients developing grade 3 or 4 neuropathy will have 
carboplatin discontinued and will be taken off study 
treatment. 
Dose Modifications for Carboplatin and 5-FU on day 1 
based on nadir during previous cycle 
 
Carboplatin 
5-FU 
1st episode* 
Dose reduce by  
1 level 
Dose reduce by 
1 dose level 
2nd episode*  
Dose reduce by  
1 level 
Dose reduce by  
1 level 
3rd episode 
Discontinue  
protocol therapy 
Discontinue  
protocol therapy 
Anemia 
No adjustment 
No adjustment 
* Episodes = 1) Febrile Neutropenia or 2) ANC< 500/mm3 or 3) 
Platelet Nadir < 25,000/mm3 
Treatment should be delayed for up to 3 weeks until the 
day 1 ANC is at least 1,500/mm3 and the platelet count is 
at least 100,000/mm3. However, if the counts have not 
recovered in 3 weeks, the patient’s protocol treatment will 
be discontinued. The patient will still be followed for toxicity 
and response. Patient and investigators need to be 
attentive to the possibility of fever and infection so that 
these complications can be promptly and appropriately 
managed. 
If chemotherapy must be withheld due to hematologic 
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least twice a week until the counts reach the lower limits 
for treatment. The treatment schedule will then proceed in 
the usual schedule. 
No dose reductions will be made for anemia. Patients 
should be supported per the treating physician’s discretion. 
The use of growth factor support for anemia will be 
allowed, as will blood transfusions as indicated. 
Dose reductions, once initiated, are permanent for all 
future cycles. If both febrile neutropenia and 
thrombocytopenia of < 25,000/mm3 occur, the dose 
reduction will be to the lower dose specified.  
5.5.5 
Bevacizumab Dose Modifications (ARM B) 
Chemotherapy dose modifications will not impact bevacizumab 
therapy (e.g., patients who require dose modification of their 
chemotherapy continue to receive bevacizumab every 3 weeks as 
initially scheduled). However, it is recommended that if toxicity ensues 
requiring holding chemotherapy or bevacizumab, all drugs are held (if 
the anticipated delay will be short), so they can be administered on 
the same day.  
If bevacizumab is discontinued permanently, chemotherapy will be 
continued alone until progression of disease.  
If chemotherapy is discontinued permanently, bevacizumab can be 
continued alone until progression of disease assuming that the patient 
has PR/CR or SD after at least 4 cycles of chemotherapy. Otherwise 
the patient will be taken off study treatment.  
5.5.5.1 
Dose Modifications for Bevacizumab Toxicities are as 
Follows: 
5.5.5.1.1 
Infusion-Related Adverse Events 
For grade 4 infusion-related reactions or 
allergic reactions bevacizumab will be 
permanently discontinued. For grade 1-3 
reactions and management of reactions see 
Section 5.5.5.1.2 below. 
5.5.5.1.2 
Dose Modifications/Delays 
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. 
Regardless of the reason for holding 
bevacizumab treatment, the maximum 
allowable length of treatment interruption is 
2 months. 
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Adverse events requiring delays or 
permanent discontinuation of bevacizumab 
are listed in the following Table. 
NOTE: 
There will be no dose reduction 
for bevacizumab. Treatment 
should be interrupted or 
discontinued for certain adverse 
events, as described below: 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE Version 4.0 
Grade 
Action to be Taken 
Allergic reactions  
or  
Infusion-related reactions 
Or  
Anaphylaxis 
Grade 1-2 
 
• 
Infusion of bevacizumab should be 
interrupted for patients who develop dyspnea 
or clinically significant hypotension.  
• 
For infusion-associated symptoms not 
specified above, infusion should be slowed to 
50% or less or interrupted. Upon complete 
resolution of the symptoms, infusion may be 
continued at no more than 50% of the rate 
prior to the reaction and increased in 50% 
increments every 30 minutes if well tolerated. 
Infusions may be restarted at the full rate 
during the next cycle.  
• 
Patients who experience bronchospasm 
(regardless of grade) should discontinue 
bevacizumab. 
G3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Arterial); arterial ischemia  
- 
Cardiac ischemia 
- 
Myocardia  infraction 
- 
CNS ischemia (TIA, 
CVA) 
- 
any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 2  
(new or worsening 
since bevacizumab 
Discontinue bevacizumab. 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Venous) 
Grade 3 
OR 
asymptomatic  
Grade 4 
• 
Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is 
<2weeks, bevacizumab should be held until 
the full-dose anticoagulation period is over. 
• 
If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during full-dose 
anticoagulation IF all of the criteria below are 
met: 
- 
The patient must not have pathological 
conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels or 
other conditions) 
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- 
The patient must not have had 
hemorrhagic events > grade 2 while on 
study 
- 
The patient must be on stable dose of 
heparin, low molecular weight heparin, 
or have an in-range INR (usually 2-3) on 
a stable dose of warfarin prior to 
restarting bevacizumab. 
• 
If thromboemboli worsen/recur upon 
resumption of study therapy, discontinue 
bevacizumab 
Grade 4 (symptomatic) Discontinue bevacizumab 
Hypertension 
 
[Treat with anti-hypertensive medication as needed.  The goal of BP 
control should be consistent with general medical practice] 
 
Grade 1 
(SBP 120-139 mmHg 
or DBP80-89 mm Hg) 
Consider increased BP monitoring; start anti-
hypertensive medication if appropriate 
 
Grade 2 
asymptomatic 
(SBP 140-159 mmHg 
or DBP 90-99 mm 
Hg) 
Begin anti-hypertensive therapy and continue 
bevacizumab 
 
• Grade 2 
symptomatic 
(SBP 140-160 
mmHg or DBP 90-
100 mm Hg) 
• Grade 3 
(≥ SBP 160 mmHg 
or ≥ DBP 100 
mmHg 
• 
Start or adjust anti-hypertensive medication 
• 
Hold bevacizumab until symptoms resolve 
AND BP < 160/90mmHg 
 
Grade 4 
(Hypertensive crisis 
or malignant 
hypertension) 
Discontinue bevacizumab 
Heart Failure or LV 
dysfunction 
Grade 3 
Discontinue bevacizumab 
Grade 4 
Discontinue bevacizumab 

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Proteinuria 
 
[Proteinuria should be monitored by urine analysis for urine protein 
creatinine (UPC) ratio or dipstick prior to every other dose of 
bevacizumab]. If dipstick shows 2 + proteinuria or more 24 hour urine 
protein should be obtained. 
UPC ratio  
< 3.5 or 24-h urine 
protein < 3.5 gm 
Continue bevacizumab. 
UPC ratio  
≥ 3.5 or 24-h urine 
protein ≥ 3.5 gm 
Hold bevacizumab until it UPC recovers to < 3.5, 
or 24-h urine protein < 3.5 gm. 
Discontinue bevacizumab if urine protein does not 
recover to < 3.5 after 8 weeks or bevacizumab 
interruption 
Nephrotic syndrome 
Discontinue bevacizumab. 
Hemorrhage (intracranial 
or pulmonary)  
Grade 2-4 
• 
Discontinue bevacizumab 
Grade 1 
• 
Hold bevacizumab until ALL of the following 
criteria are met: 
- 
the bleeding has resolved and Hb is 
stable 
- 
there is no bleeding diathesis that 
would increase the risk of therapy 
- 
there is no anatomic or pathologic 
condition that could increase the risk of 
hemorrhage recurrence 
Hemorrhage (any other 
organ system) 
Grade 3 
 
• 
Hold bevacizumab until ALL of the following 
criteria are met: 
- 
the bleeding has resolved and Hb is 
stable 
- 
there is no bleeding diathesis that 
would increase the risk of therapy 
- 
there is no anatomic or pathologic 
condition that could increase the risk of 
hemorrhage recurrence. 
• 
Patients who experience recurrence of grade 
3 hemorrhage should discontinue study 
therapy. 
 
Grade 4 
• 
Discontinue bevacizumab 
RPLS (Reversible Posterior Leukoencephalopathy 
syndrome or PRES (Posterior Reversible 
Encephalopathy Syndrome) 
• 
Hold bevacizumab in patients with 
symptoms/signs suggestive of RPLS; 
subsequent management should include 
MRI scans and control of HTN. 
• 
Discontinue bevacizumab upon diagnosis of 
RPLS. 
Wound dehiscence requiring medical or surgical 
intervention 
• 
Discontinue bevacizumab 
Perforation (GI, or any other organ) 
• 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any other organ) 
• 
Discontinue bevacizumab 
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Obstruction of GI tract 
G2 requiring medical 
intervention 
• 
Hold bevacizumab until complete resolution  
 
G3-4 
• 
Hold bevacizumab until complete resolution 
• 
If surgery is required, patient may restart 
bevacizumab after full recovery from surgery, 
and at investigator’s discretion 
Other Unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
• 
Hold bevacizumab until symptoms resolve to  
≤ grade 1 
Grade 4 
• 
Discontinue bevacizumab 
• 
Upon consultation with the study chair, 
resumption of bevacizumab may be 
considered if a patient is benefiting from 
therapy, and the G4 toxicity is transient, has 
recovered to  
≤ grade 1 and unlikely to recur with 
retreatment. 
5.5.6 
Carboplatin Substitution 
Patients developing the following cisplatin-induced toxicities will 
discontinue cisplatin and substitute Carboplatin, AUC 6, administered 
as a 30-minute infusion on day 1, every 21 days, using the following 
formula to calculate the total dose:  
NOTE: 
Carboplatin will be given at an AUC of 5, if there has been 
already a dose reduction by one level in the starting dose 
of any of the two drugs of the cisplatin doublet, and AUC of 
3.5, if there have been 2 previous dose reductions in the 
starting dose any of the two drugs of the cisplatin doublet.  
5.5.6.1 
Calculation of Carboplatin Dose 
The dose of Carboplatin during chemotherapy will be 
calculated using the following formula (Calvert equation): 
Carboplatin total dose in mg = AUC x (glomerular 
filtration rate  
[GFR] +25) 
NOTE: 
When calculating carboplatin dose, GFR should 
not exceed 125 mL/min. Thus, the maximum 
carboplatin dose for AUC of 6 will be 900 mg.  
Calculated creatinine clearance (CrCl) will be used to 
estimate the GFR. The modified Cockcroft-Gault formula 
below should be used to calculate the creatinine 
clearance. 
140 – age (years) x actual weight (kg) / 72 x Serum 
creatinine (mg/dL) (for females, multiply the result by 
0.85) 
The actual weight will be used for the calculation of 
Creatinine Clearance.   
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5.5.6.2 
Toxicities requiring carboplatin substitution 
1) Persistent grade 2 sensory or motor neuropathy for > 1 
week 
2) Nephrotoxicity with creatinine clearance < 50 mL/min 
on the day of schedule chemotherapy administration 
that lasts ≥ 1 week, a rise in serum creatinine to > 4 
mg/dL at any time, or persistent/refractory 
hypomagnesemia or other electrolyte imbalances and 
severe kidney abnormalities that can be attributed to 
cisplatin. 
3) Grade 2 ototoxicity (persistent): Carboplatin may also 
cause ototoxicity. If hearing loss worsens while on 
carboplatin, the patient should be presented with a 
discussion of the relative risks of hearing loss versus 
the potential benefit of receiving carboplatin therapy. 
Severe hearing loss (grades 3 or 4) is an indication to 
discontinue the carboplatin. 
4) Grade 4 nausea and vomiting attributed to cisplatin 
despite appropriate antiemetics 
5.5.6.3 
Carboplatin Dose Modifications 
1) Carboplatin will be administered if platelets are  
≥ 100,000 cells/mm3 above and ANC is 1500 ≥ 
cells/mm3. Treatment will be delayed up to 3 weeks 
until the above criteria are met. 
2) 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, carboplatin dose will be reduced 
to AUC of 4.5 in all subsequent administrations. A 
second dose reduction to AUC of 3 is allowed. 
3) Patients developing grade 3 or 4 neuropathy will have 
carboplatin discontinued and will be taken off study 
treatment. 
5.6 
Prophylactic Medication Regimen 
5.6.1 
Corticosteroid premedication 
The following premedication regimen must be administered for all 
patients treated with docetaxel 
Dexamethasone 8 mg orally, twice a day, starting the night (i.e. 
approximately 12 hours prior to docetaxel) prior to docetaxel for a total 
of 6 doses (see 5.1.1.2 for additional antiemetic dexamethasone 
treatment). On the day docetaxel is given, a higher dose of 
dexamethasone (10-20 mg) is recommended as part of antiemetic 
therapy. Please refer to 5.1.1. 
It is recommended that all regimen patients continue 
dexamethasone for 1-2 additional days (as an antiemetic for 
delayed emesis). Refer to 5.1.1.2. 
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Patients on cisplatin/5-FU may start dexamethasone the day after 
cisplatin and receive it for a total of 3-4 days. Refer to 5.1.2.3. 
5.6.2 
Prophylactic Antibiotic Therapy 
All patients treated on study must receive prophylactic antibiotic 
therapy. 
Ciprofloxacin (or alternate) is recommended at 500 mg p.o. twice a 
day for 10 days starting on day 5 of each cycle of chemotherapy. 
5.7 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.7.1 
Concomitant Therapy and Drugs 
No other chemotherapy, immunotherapy, antitumor hormonal therapy 
(excluding contraceptives and replacement steroids), radiation 
therapy, or experimental medications will be permitted while the 
patients are on the study.  Any disease progression requiring other 
forms of specific antitumor therapy will be cause for early 
discontinuation in this study.   
Antiemetics and erythropoietin will be allowed at the discretion of the 
treating physician.  
NOT ALLOWED: 
a. Amifostine is not allowed. 
b. Concomitant treatment with bisphosphonates in case of bone 
metastasis is not permitted unless treatment was initiated more 
than three months before study entry. 
5.7.2 
Surgery 
If surgery is considered necessary for the patient, whenever possible, 
at least 28 days should elapse after the last dose of bevacizumab 
before surgery is performed (Arm B). 
5.7.3 
Other Supportive Care  
5.7.3.1 
All supportive measures consistent with optimal patient 
care will be given throughout the study. 
5.7.3.2 
The clinical tolerance of the patients, the overall tumor 
response, and the medical judgment of the investigator will 
determine if it is in the patient’s best interest to continue or 
discontinue treatment. If treatment is discontinued due to 
any toxicity, the patient must be followed to monitor 
duration of toxicity, response and time to progression, until 
the initiation of any new systemic therapy. 
5.7.3.3 
Suggested supportive care medications may be substituted 
at the discretion of the investigator based on drug 
availability. 
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5.7.3.4 
Hyperalimentation may be used, but details must be clearly 
outlined on treatment forms. 
5.7.3.5 
Concomitant aminoglycoside antibiotic use should be 
avoided. 
5.7.3.6 
Recombinant erythropoietin or similar compound may be 
administered for symptomatic and/or progressive > grade 2 
anemia. 
5.7.3.7 
If G-CSF is used, it must be used in accordance with the 
American Society of Clinical Oncology (ASCO) guidelines 
as published in the Journal of Clinical Oncology (ASCO, 
2006). 
5.7.3.8 
Diarrhea may occur on either arm. Appropriate supportive 
measures including Imodium and/or Lomotil should be 
implemented immediately to prevent dehydration. 
5.7.3.9 
Hydration guidelines may be modified at the discretion of 
the treating physician provided adequate pre and post 
cisplatin hydration is achieved and renal function remains 
adequate.  
Antiemetic therapy is critical for proper administration of 
cisplatin (refer to 5.1.1.2 and 5.1.2.3). The specific anti-
emetic regimen is at the discretion of the treating 
physician, provided adequate control is achieved.  
However, on day of cisplatin therapy the investigator 
should consider use of a steroid medication and a 5HT3 
antagonist. One such regimen consists of 20 mg of 
dexamethasone and a high dose of a 5HT3 antagonist 
(such as 2 mg oral of 10 mcg/kg IV granisetron or 32 mg 
ondansetron or equivalent) and continuing with 4 days of 
dexamethasone or equivalent steroid and 4 days of 
scheduled anti-emetic such as metoclopramide or a 5HT3 
antagonist. If this regimen is ineffective, consideration of 
the long-acting 5HT3 antagonist palonosetron and the 
agent aprepitant should be considered at the discretion of 
the investigator.    
5.8 
Management Of Docetaxel Adverse Events 
5.8.1 
Management of Hyperlacrimation 
The following guidelines may be taken for patients experiencing 
clinically significant hyperlacrimation: 
1. Withhold docetaxel treatment until resolution. 
2. Frequent instillation of artificial tears. 
3. Prescribe a steroid ophthalmic solution (e.g. prednisolone acetate) 
2 gtts each eye bid for 3 days starting the day before docetaxel 
administration in patients without a history of herpetic eye disease. 
4. Ophthalmologist consult 
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5.8.2 
Management of Fluid Retention Syndrome 
There are no dose reductions for fluid retention. 
Patients developing new onset edema, progression of existing edema, 
or another sign of fluid retention (e.g. 2 pound weight gain) are to be 
treated with oral diuretics.  Regimens found to be effective in the 
management of fluid retention due to docetaxel are listed below.  
Triamterene/hydrochlorothiazide one capsule 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 trial, furosemide 40 mg po qd is ineffective, the 
patient may be treated with furosemide 20 mg po daily plus 
metolazone 2.5 mg po daily with potassium supplementation as 
needed. 
Further therapy should be customized depending upon the clinical 
situation.  The clinical tolerance of the patient, the overall tumor 
response and the medical judgment of the investigator will determine 
if it is in the patient’s best interest to continue or discontinue 
treatment. 
5.8.3 
Other Non-Hematologic Toxicities 
For grade 3 or 4 toxicities not listed here, treatment should be 
withheld until the toxicity resolves to grade 1 or less, then reinstituted 
(if medically appropriate).  (See Dose Modification Section) 
5.8.4 
Infusion Related Reactions or Allergic Reactions 
Discontinue protocol treatment for Grade 3 or 4 infusion related 
reactions or allergic reactions. There are no dose reductions for 
infusion related reactions or allergic reactions. 
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Hypersensitivity reactions will be managed according to the following 
guidelines:  
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: 
localized cutaneous 
reactions such as mild 
pruritus, flushing, rash 
Consider decreasing the rate of infusion until recovery from symptoms, stay 
at bedside and monitor patient.  Then, complete 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 
pruritus, flushing, rash, 
dyspnea, hypotension 
with systolic BP > 80 
mm Hg 
Interrupt docetaxel infusion 
Give diphenhydramine 50 mg IV with or without dexamethasone 10 mg IV; 
monitor patient until resolution of symptoms 
Resume docetaxel infusion after recovery of symptoms; depending on the 
physician’s assessment of the patient, docetaxel infusion should be resumed 
at a slower rate, then increased incrementally to the initial planned rate (e.g., 
Infuse at an 8 hour rate for 5 minutes, then at a 4-h rate for 5 minutes, then 
at a 2h rate for 5 minutes, then finally, resume at the 1h infusion rate) 
Depending on the intensity of the reaction observed, additional oral or IV 
premedication with anti-histamine 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, (e.g., Infuse at an 8 
hour rate for 5 minutes, then at a 4-h rate for 5 minutes, then at a 2-h rate for 
5 minutes, and finally, administer at the 1-h infusion rate) 
Severe symptoms: any 
reaction such as 
bronchospasm, 
generalized urticaria, 
systolic BP < 80mm 
Hg, angioedema 
Immediately discontinue docetaxel infusion  
Give diphenhydramine 50 mg IV with or without dexamethasone 10 mg IV 
and/or epinephrine as needed; monitor patient until resolution of symptoms 
The same treatment guidelines outlined under moderate symptoms should 
be followed. 
Grade 3 or 4 infusion 
related reactions or 
allergic reactions 
DISCONTINUE PROTOCOL TREATMENT* 
In case of a severe life-threatening anaphylactic reaction, docetaxel 
will not be re-administered and hence docetaxel will be discontinued. 
Following an infusion related reaction or allergic reaction, and 
depending on its severity, additional oral or IV premedication with an 
antihistamine should be given prior to the next administration and the 
rate of the infusion should be increased gradually to the 
recommended 1-hour infusion rate (e.g. infuse at an 8 hour rate for 5 
minutes, then at a 4-hour rate for 5 minutes, then at a 2-hour infusion 
rate for 5 minutes, then finally, resume at the 1-hour infusion rate). 
* In case of prolonged or recurrent 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. 
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5.9 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
Arm A: Protocol therapy until tumor progression.  At the discretion of the treating 
physician, chemotherapy may be discontinued after 6 cycles if there is maximum 
response (i.e. no further improvement in tumor measurements for 2 or more 
cycles).  
Arm B: Protocol therapy until tumor progression.  At the discretion of the treating 
physician, chemotherapy may be discontinued after 6 cycles if there is maximum 
response (i.e. no further improvement in tumor measurements for 2 or more 
cycles). 
Patients may be removed from study therapy if: 
• 
Unacceptable adverse events (please refer to dose modifications/delay 
guidelines in Section 5.5 through 5.7) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.10 
Duration of Follow-up 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for survival for 5 years from the date of registration. All 
patients must also be followed through completion of all protocol therapy. 
 

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6. 
Measurement of Effect 
6.1 
Solid Tumor Response Criteria (RECIST)  
6.1.1 
Malignant Disease Evaluation  
To assess objective response, it is necessary to estimate the overall 
tumor burden at baseline to which subsequent measurements will be 
compared. Measurable disease is defined by the presence of at least 
one measurable lesion. 
All measurements should be recorded in metric notation by use of a 
ruler or calipers. The same method of assessment and the same 
technique should be used to characterize each identified lesion at 
baseline and during follow-up. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and 
never more than four weeks before registration. 
The term evaluable in reference to measurability will not be used 
because it does not provide additional meaning or accuracy. 
At baseline, tumor lesions will be characterized as either measurable 
or non-measurable. 
6.1.1.1 
Measurable  
Lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm 
(2.0 cm) with conventional techniques or as ≥ 10 mm (1.0 
cm) with spiral CT scan. 
If the measurable disease is restricted to a solitary lesion, 
its neoplastic nature should be confirmed by 
cytology/histology. 
6.1.1.2 
Non-Measurable  
All other lesions, including small lesions [longest diameter 
< 20 mm (2.0 cm) with conventional techniques or < 10 
mm (1.0 cm) with spiral CT scan] and truly non-
measurable lesions. 
Lesions considered to be truly non-measurable include the 
following: bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are 
not confirmed and followed by imaging techniques, and 
cystic lesions. 
Tumor lesions that are situated in a previously irradiated 
area might or might not be considered measurable. The 
conditions under which such lesions should be considered 
must be defined in the protocol when appropriate (Section 
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6.1.2 
Definitions of Response – Target Lesions  
All measurable lesions up to a maximum of five lesions per organ and 
10 lesions in total, representative of all involved organs. Target 
lesions should be selected on the basis of their size (those with the 
longest diameters) and their suitability for accurate repeated 
measurements. 
The sum of the longest diameters of all target lesions will be 
calculated at baseline and reported as the baseline sum longest 
diameter. The sum longest diameter will be used to characterize the 
objective tumor response. For lesions measurable in 2 or 3 
dimensions, always report the longest diameter at the time of each 
assessment. 
6.1.2.1 
Complete Response (CR)  
The disappearance of all target lesions. To be assigned a 
status of complete response, changes in tumor 
measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for 
response are first met. 
6.1.2.2 
Partial Response (PR)  
At least a 30% decrease in the sum of the longest 
diameters of target lesions, taking as reference the 
baseline sum longest diameter. To be assigned a status of 
partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than 
four weeks after the criteria for response are first met. 
6.1.2.3 
Progressive Disease (PD) 
At least a 20% increase in the sum of the longest 
diameters of target lesions, taking as reference the 
smallest sum longest diameter recorded since the baseline 
measurements, or the appearance of one or more new 
lesion(s). 
6.1.2.4 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for partial response 
nor sufficient increase to qualify for progressive disease. 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after study entry at a minimum interval of six weeks.  
6.1.3 
Definition of Response - Nontarget Lesions  
All other lesions or sites of disease. Measurements of these lesions 
are not required, but the presence or absence of each should be 
noted throughout follow-up. 
6.1.3.1 
Complete Response (CR)  
The disappearance of all nontarget lesions and 
normalization of tumor marker levels, if applicable. To be 

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assigned a status of complete response, changes in tumor 
measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for 
response are first met. 
6.1.3.2 
Incomplete Response/Stable Disease (SD)  
The persistence of one or more nontarget lesion(s) and/or 
the maintenance of tumor marker levels above the normal 
limits. To be assigned a status of stable disease, 
measurements must have met the stable disease criteria at 
least once after study entry at a minimum interval of six 
weeks.  
6.1.3.3 
Progressive Disease (PD)  
The appearance of one or more new lesion(s) and/or 
unequivocal progression of existing nontarget lesions. 
6.1.4 
Symptomatic Deterioration  
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be classified as having symptomatic 
deterioration. 
6.2 
Evaluation of Patient's Best Overall Response  
The best overall response is the best response recorded from registration until 
disease progression/recurrence, taking as reference for progressive disease the 
smallest measurements recorded since registration. The table below provides 
overall responses for all possible combinations of tumor responses in target and 
nontarget lesions, with or without new lesions. 
To be assigned a status of complete or partial response, changes in tumor 
measurements must be confirmed by repeat assessments performed no less 
than four weeks after the criteria for response are first met. 
To be assigned a status of stable disease, measurements must have met the 
stable disease criteria at least once after study entry at a minimum interval of six 
weeks. 
Overall Response for all Possible Combinations of Tumor Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 

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6.2.1 
First Documentation of Response  
The time between initiation of therapy and first documentation of PR 
or CR. 
6.2.2 
Confirmation of Response  
To be assigned a status of complete or partial response, changes in 
tumor measurements must be confirmed by repeat assessments 
performed no less than four weeks after the criteria for response are 
first met. 
6.2.3 
Duration of Response  
Duration of overall response – the period measured from the time that 
measurement criteria are met for complete or partial response 
(whichever status is recorded first) until the first date that recurrent or 
progressive disease is objectively documented, taking as reference 
the smallest measurements recorded since treatment started. 
6.2.3.1 
Duration of Overall Complete Response  
The period measured from the time measurement criteria 
are met for complete response until the first date that 
recurrent disease is objectively documented. 
6.2.3.2 
Duration of Stable Disease  
A measurement from registration until the criteria for 
disease progression is met, taking as reference the 
smallest measurements recorded since registration. To be 
assigned a status of stable disease, measurements must 
have met the stable disease criteria at least once after 
study entry at a minimum interval of six weeks.  
6.2.4 
Survival  
Survival will be measured from the date of entry on study.  
6.2.5 
Time to Progression  
This interval will be measured from the date of entry on the study to 
the appearance of new metastatic lesions or objective tumor 
progression. 
6.2.6 
Methods of Measurement  
Imaging based evaluation is preferred to evaluation by clinical 
examination. The same imaging modality must be used throughout 
the study to measure disease. 
6.2.6.1 
CT and MRI  
CT and magnetic resonance imaging (MRI) are the best 
currently available and most reproducible methods for 
measuring target lesions. Conventional CT and MRI should 
be performed with contiguous cuts of 10 mm or less in 
slice thickness. Spiral CT should be performed by use of a 
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specification applies to tumors of the chest, abdomen, and 
pelvis, while head and neck tumors, and those of the 
extremities require specific procedures. 
6.2.6.2 
Chest X-Ray  
Lesions on chest x-ray are acceptable as measurable 
lesions when they are clearly defined and surrounded by 
an aerated lung. However, CT is preferable. 
6.2.6.3 
Tumor Markers  
Tumor markers alone cannot be used to assess response. 
If initially above the upper normal limit, a tumor marker 
must return to normal levels for a patient to be considered 
in complete clinical response when all tumor lesions have 
disappeared. 
6.2.6.4 
Clinical Examination  
Clinically detected lesions will only be considered 
measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For skin lesions, 
documentation by color photography, including a ruler to 
estimate size of the lesion, is recommended. Photographs 
should be retained at the institution. 
6.2.6.5 
Cytology and Histology  
Cytologic and histologic techniques can be used to 
differentiate between complete and partial response in rare 
cases (e.g., after treatment to differentiate residual benign 
lesions and residual malignant lesions in germ cell tumors). 
Cytologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is 
required when the measurable tumor has met response or 
stable disease criteria. 
6.2.6.6 
Endoscopy and Laparoscopy  
Endoscopy and laparoscopy have not been fully or widely 
validated, so their use should be limited to validation 
studies in specialized institutions, and to confirming 
complete histopathologic response when biopsy 
specimens have been obtained. 
6.2.6.7 
Ultrasound  
Ultrasound may be used only as an alternative to clinical 
measurements for superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules, and for 
confirming complete disappearance of superficial lesions 
usually assessed by clinical examination.  
 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done  
≤ 4 weeks prior to randomization. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 2 weeks before randomization.  
3. All required prestudy chemistries, as outlined in Section 3, should be done ≤ 2 weeks before randomization – unless 
specifically required on Day 1 as per protocol.  
NOTE: 
Pre study labs may not stand-in for labs required on day 1 of treatment unless conducted within 24 hours of 
treatment. 
NOTE: 
Please See Section 7.2 for correlative/pathology sample requirements. 
Table 7.1.1: Study Parameters 
 
 
Baseline 
Prior to Each 
Chemo Treatment 
Cycle Day 1 
Every 2 Chemo 
Treatment Cycles 
Q cycle prior to trt on Bevacizumab 
only cycles(Arm B only)9 
Post Treatment to 5 years 
from study entry1 
 
History and Physical exam,  
Vital Signs 
X 
X 
 
X 
X 
 
Height and weight 
X 
X2 
 
X2 
X2 
 
Performance Status 
X 
X 
 
X 
X 
 
CBC, Differential, Platelets 
X 
X3 
 
X (Q 2 cycles) 
X 
 
Serum Creatinine, Electrolytes 
(K+,Na+,Cl-,CO2), Calcium, Mg++ 
X 
X 
 
X (Q 2 cycles) 
X 
Rev. 11/11 
Urine dipstick or Urine Protein 
Creatinine(UPC) (after baseline, 
for Arm B ONLY)10 
X 
 
X (for Arm B only) 
X(Q 2 cycles) 
 
 
Liver function tests 4 
X 
X 
 
X(Q 2 cycles) 
X 
 
CT chest 
X 
 
X 
X(Q 2 cycles) 
X 
 
CT or MRI of the neck 
X 
 
X 
X (Q 2 cycles) 
X 
 
EKG 
X 
 
 
 
 
 
PT/PTT 7 
X 
 
 
 
 
 
Pregnancy test 5  
X 
 
 
 
 
 
Tumor Measurements 6 
X 
 
X 
X9 
X8 
 
Correlative/banking samples 
See Section 7.2 for correlative sample requirements 
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1 
Patients will be followed every 3 months if patient is < 2 years from study entry then every 6 months if patient is 2-5 years from study entry. No specific 
requirements if patient is more than 5 years from study entry.  
2 
Weight only. 
3 
Complete blood counts with differential and platelet count should be performed <24 hours prior to chemotherapy administration. In the event of grade 3 or 4 
hematologic toxicity, follow-up CBC with differential and platelet count will be obtained every 1-3 days until there is evidence of hematologic recovery. 
4 
Liver function tests should include: Total bilirubin, SGOT (AST), SGPT (ALT), and alkaline phosphatase. 
5 
All females of childbearing potential must have a negative pregnancy test or urinalysis done < 2 weeks prior to randomization to rule out pregnancy. 
6 
Tumor measurements may be made using physical examination, CT scans or MRI scans. Tumor measurement by CT/MRI scans to be done every 2 cycles.  
Repeat imaging should be with the same modality.  In case of treatment delays it is suggested that the patient receives the planned number of cycles and then 
undergo evaluation of disease.  When the patient is deemed to have an objective response (CR or PR), tumor measurements will be repeated 4 weeks later to 
confirm the response.  See Section 6.2.2. 
7 
Recheck PT/PTT if clinically indicated (e.g. patients on prophylactic warfarin 1 g QD). 
8 
Arm A: Patients who have completed chemotherapy and have not progressed will be followed every 6 weeks (every 2 cycles) x 2 times, then every 9 weeks until 
progression. Thereafter, patients will be followed as in footnote 1. No further tumor measurements are required after documented disease progression.  
9 
Arm B: Patients who have completed chemotherapy and have not progressed will continue to receive bevacizumab every cycle until progression.  Patients will 
have tumor assessment every 6 weeks (every 2 cycles) x 2 times, then every 9 weeks until progression. 
10 Proteinuria should be monitored by urine analysis for urine protein creatinine (UPC) ratio or dipstick prior to every other dose of bevacizumab. If 
dipstick shows 2+ proteinuria or more, 24 hour urine protein should be obtained. 
 
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7.2 
Biological Sample Submissions 
Collection and submission of samples for correlative studies and banking for 
future research are to be limited to those patients who have given written 
informed consent for their materials to be used for these purposes. See Section 
10. 
NOTE: 
All specimens submitted must be entered and tracked via the online 
ECOG-ACRIN Sample Tracking System (STS). See Section 10.1.5. 
NOTE: 
Due to the importance of translational research associated with 
targeted therapies, patients should be strongly encouraged to 
participate in the correlative studies and banking. 
7.2.1 
NOTE: 
Blood samples are to be drawn in the order listed. 
 
Pre-study 
Cycle 2, 
Day 1 
Paraffin embedded tumor1 
X 
 
Serum (one 10 mL red top tube)2 
X 
X 
Plasma (two 10 mL EDTA purple top tubes)2  
X 
X 
Peripheral blood (one 10 mL EDTA purple top tube)2 
X 
X 
Peripheral blood (PAXgene DNA tube)2 
X 
 
Peripheral blood (PAXgene RNA tube)2 
X 
X 
1 
Submit with STS generated shipping manifest, pathology reports 
and immunological reports 
2 
Kits for sample collection and shipment are available for sites in 
the United States and Canada. Complete the KIT ORDER FORM  
(Appendix V) and fax to Zemotak-International at (800) 815-4675. 
NOTE: 
Institutions outside the United States and Canada are 
not required to participate in the fresh tissue (blood 
samples) studies because of the costs and problems 
associated with international shipping. 
 
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8. 
Drug Formulation and Procurement 
8.1 
Bevacizumab (NSC 704865) 
8.1.1 
Other Names 
rhuMAb VEGF 
8.1.2 
Classification 
Recombinant humanized monoclonal antibody 
8.1.3 
Molecular Weight 
Approximate molecular weight is 149,000 daltons 
8.1.4 
Mode of Action 
Bevacizumab blocks the binding of vascular endothelial growth factor 
(VEGF) to its receptors resulting in inhibition of angiogenesis. 
8.1.5 
Description 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal 
antibody, consisting of 93% human and 7% murine amino acid 
sequences.  The agent is composed of human IgG framework and 
murine antigen-binding complementarity-determining regions. 
8.1.6 
How Supplied 
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid 
ready for parenteral administration in two vial sizes: 
Each 100 mg (25 mg/mL – 4 mL fill) glass vial contains bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for 
Injection, USP. 
Each 400 mg (25mg/ml – 16 mL fill) glass vial contains bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for 
Injection, USP. 
8.1.7 
Preparation 
Vials contain no preservatives and are intended for single use only. 
Add the appropriate volume of bevacizumab to a commercially 
prepared 100 mL bag of 0.9% sodium chloride.  
8.1.8 
Storage 
Upon receipt, bevacizumab should be refrigerated (2º to 8º C). Do not 
freeze.  Do not shake. 
8.1.9 
Stability 
Shelf-life studies of rhuMAb VEGF are ongoing. The sterile single use 
vials contain no antibacterial preservatives. Therefore, vials should be 
discarded 8 hours after initial entry. 
Once diluted in 0.9% sodium chloride, solutions of bevacizumab must 
be administered within 8 hours. 

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8.1.10 
Route of Administration 
Intravenous 
8.1.11 
Method of Administration 
The initial dose should be administered over a minimum of 90 
minutes. If no adverse reactions occur, the second dose should be 
administered over a minimum of 60 minutes. If no adverse reactions 
occur after the second dose, all subsequent doses should be 
administered over a minimum of 30 minutes. If infusion-related 
adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated.  
To insure complete delivery of bevacizumab, the IV infusion line must 
be flushed with 0.9% sodium chloride. The following are two 
recommended methods for flushing the bevacizumab IV infusion line: 
1. When the bevacizumab infusion is complete, add an additional 
50mL of 0.9% sodium chloride 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. 
2. Replace the empty bevacizumab 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. 
8.1.12 
Availability 
Bevacizumab is an investigational agent (BB IND #7921) supplied to 
investigators by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. 
Bevacizumab is provided to the NCI under a Cooperative Research 
and Development Agreement (CRADA) between Genentech, Inc. 
and the NCI Division of Cancer Treatment and Diagnosis (DCTD).  
(See Appendix VII.) 
8.1.13 
Agent Ordering 
NCI-supplied agents may be requested by the Principal Investigator 
(or their authorized designees) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that the 
agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).   
The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The responsible investigator at 
each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied 
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investigational agents for the study should be ordered under the name 
of one lead investigator at that institution. 
Active CTEP-registered investigators and investigator-designated 
shipping designees and ordering designees can submit agent 
requests through the PMB Online Agent Order Processing (OAOP) 
application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password. 
8.1.14 
Agent Accountability 
The Investigator, or a responsible party designated by the 
Investigator, must maintain a careful record of the inventory and 
disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form.  See the CTEP web site for Policy and 
Guidelines for Accountability and Storage of Investigational Drugs 
(http://ctep.cancer.gov/requisition/storage.html). 
8.1.15 
Patient Care Implications 
Measurement of blood pressure should be performed prior to each 
dose of bevacizumab. Modification of dose or discontinuation of 
therapy should be considered if the patient experiences uncontrolled 
hypertension. Urine protein creatinine will be checked at baseline and 
every other bevacizumab cycle as specified in the Study Parameters 
Table (see 7.1.1). 
Monitor patient closely during infusion, for infusion related events and 
for bleeding. Instruct patient to monitor and report signs of bleeding, 
increased cough, swelling.  
Treat pain, arthralgias, etc. with acetaminophen, or other pain relief 
strategies that do not interfere with the clotting cascade.  
8.1.16 
Side Effects 
Please see Section 5.4 
8.2 
Docetaxel  - (Please refer to the package insert for further information) 
8.2.1 
Other Names 
Taxotere, RP 56976, NSC #628503. 
8.2.2 
Classification 
Antimicrotubule agent. 
8.2.3 
Mode of Action 
Docetaxel, a semisynthetic analog of taxol, promotes the assembly of 
tubulin and inhibits microtubule depolymerization.  Bundles of 
microtubules accumulate and interfere with cell division. 
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8.2.4 
Storage and Stability 
Docetaxel infusion solution, if stored between 2 and 25ºC (36 and 
77ºF) is stable for 4 hours.  Fully prepared docetaxel infusion solution 
(in either 0.9% Sodium Chloride solution or 5% Dextrose solution) 
should be used within 4 hours (including the administration time). 
Store between 2 and 25°C (36 and 77ºF).  Retain in the original 
package to protect from bright light.  Freezing does not adversely 
affect the product.   
8.2.5 
Dose Specifics 
Docetaxel will be administered as a 60 minute intravenous infusion. 
Dose will be calculated based on the patient’s actual body weight.   
8.2.6 
Preparation 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially 
toxic compounds, caution should be exercised when handling and 
preparing docetaxel solutions. The use of gloves is recommended.
  
If docetaxel concentrate, initial diluted solution, or final dilution for 
infusion should come into contact with the skin, immediately and 
thoroughly wash with soap and water. If docetaxel concentrate, initial 
diluted solution, or final dilution for infusion should come into contact 
with mucosa, immediately and thoroughly wash with water. 
Docetaxel for Injection Concentrate requires two dilutions prior to 
administration. Please follow the preparation instructions provided 
below.  
NOTE: 
Both the docetaxel for Injection Concentrate and the 
diluent vials contain an overfill. 
A. 
Preparation of the Initial Diluted Solution  
1. Gather the appropriate number of vials of docetaxel for 
Injection Concentrate and diluent (13% Ethanol in Water for 
Injection).  If the vials were refrigerated, allow them to stand 
at room temperature for approximately 5 minutes.  
2. Aseptically withdraw the contents of the appropriate diluent 
vial into a syringe and transfer it to the appropriate vial of 
docetaxel for Injection Concentrate. If the procedure is 
followed as described, an initial diluted solution of 10mg 
docetaxel/mL will result. 
3. Mix the initial diluted solution by repeated inversions for at 
least 45 seconds to assure full mixture of the concentrate 
and diluent. Do not shake.  
4. The initial diluted docetaxel solution (10 mg docetaxel/mL) 
should be clear; however, there may be some foam on top of 
the solution due to the polysorbate 80. Allow the solution to 
stand for a few minutes to allow any foam to dissipate. It is 
not required that all foam dissipate prior to continuing the 
preparation process.  

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The initial diluted solution may be used immediately or 
stored either in the refrigerator or at room temperature for a 
maximum of 8 hours.  
B. 
Preparation of the Final Dilution for Infusion  
1. Aseptically withdraw the required amount of initial diluted 
docetaxel solution (10mg docetaxel/mL) with a calibrated 
syringe and inject into an infusion bag or bottle of either 
0.9% Sodium Chloride solution or 5% Dextrose solution to 
produce a final concentration of 0.3 to 0.74mg/mL. 
Thoroughly mix the infusion by manual rotation.  
2. As with all parenteral products, docetaxel should be 
inspected visually for particulate matter or discoloration prior 
to administration whenever the solution and container 
permit. If the docetaxel for Injection, initial diluted solution, or 
final dilution for infusion is not clear or appears to have 
precipitation, these should be discarded.  
The final docetaxel dilution for infusion should be administered 
intravenously as per protocol under ambient room temperature and 
lighting conditions. 
Contact of the docetaxel concentrate with plasticized PVC equipment 
or devices used to prepare solutions for infusion is not recommended. 
In order to minimize patient exposure to the plasticizer DEHP (di-2-
ethylhexyl phthalate), which may be leached from PVC infusion bags 
or sets, the final docetaxel dilution for infusion should be stored in 
bottles (glass, polypropylene) or plastic bags (polypropylene, 
polyolefin) and administered through polyethylene-lined administration 
sets. 
8.2.7 
Route of Administration 
Docetaxel will be administered as a 60 minute infusion in saline or 
D5W through an administration set that does not contain phthalate 
plasticizers along the fluid pathway that is connected to the patient’s 
vascular access catheter. 
8.2.8 
Incompatibilities 
Contact of the undiluted concentrate with plasticized PVC equipment 
or devices used to prepare solutions for infusion should be avoided. 
Diluted docetaxel solution should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and 
administered through polyethylene-lined administration sets. (See 
Sec. 8.2.6.b). 
The metabolism of docetaxel may be modified by the concomitant 
administration of compounds that induce, inhibit, or are metabolized 
by cytochrome P450 3A4, such as cyclosporine, terfenadine, 
ketoconazole, erythromycin, and troleandomycin. Caution should be 
exercised with these drugs when treating patients receiving docetaxel 
as there is a potential for a significant interaction.  

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8.2.9 
Availability 
Docetaxel (Taxotere®) is commercially available.  
Docetaxel for Injection Concentrate is supplied in a single-dose vial as 
a sterile, pyrogen-free, non-aqueous, viscous solution with an 
accompanying sterile, non-pyrogenic, diluent (13% ethanol in Water 
for Injection) vial. The following strengths are available: 
TAXOTERE 80 mg (NDC 0075-8001-80)  
TAXOTERE (docetaxel) 80 mg Concentrate for Infusion: 80 mg 
docetaxel in 2 mL polysorbate 80 and diluent for TAXOTERE 80 mg. 
13% (w/w) ethanol in Water for Injection. Both items are in a blister 
pack in one carton. 
TAXOTERE 20 mg (NDC 0075-8001-20)  
TAXOTERE (docetaxel) 20 mg Concentrate for Infusion: 20 mg 
docetaxel in 0.5 mL polysorbate 80 and diluent for TAXOTERE 20 
mg. 13% (w/w) ethanol in Water for Injection. Both items are in a 
blister pack in one carton. 
8.2.10 
Side Effects 
Cardiac: 
arrhythmias, pericardial effusions. 
Hematologic:  
dose-related neutropenia, leukopenia, 
thrombocytopenia, anemia, hypoglycemia, 
hypernatemia. 
Gastrointestinal: 
nausea and vomiting, diarrhea, oral mucositis, 
pancreatitis, esophagitis. 
Neurologic: 
reversible dysthesias or paresthesias, peripheral 
neuropathy, mild or moderate lethargy or 
somnolence, headache, seizures. 
Hypersensitivity: 
hypersensitivity (local or general skin rash, 
flushing, pruritus, drug-fever, chills and rigors, low 
back pain), severe anaphylactoid reactions 
(flushing with hypo- or hypertension, with or 
without dyspnea). 
Dermatologic: 
alopecia, desquamation following localized 
pruriginous maculopapular eruption, skin erythema 
with edema, extravasation reaction (erythema, 
swelling, tenderness, pustules), reversible 
peripheral phlebitis, nail changes. 
Hepatic: 
increased transaminase, alkaline phosphatase, 
bilirubin; hepatic failure; hepatic drug reaction. 
Pulmonary:  
dyspnea with restrictive pulmonary syndrome, 
pleural effusions. 
Other:  
asthenia, dysgeusia, anorexia, conjunctivitis, 
arthralgia, muscle aches, myopathy, peripheral 
edema, fluid retention syndrome, ascites. 

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8.2.11 
Nursing/Patient Implications 
1. Monitor CBC with differential and platelet count prior to drug 
administration.  
2. Symptom management of expected nausea, vomiting, and 
mucositis. 
3. Advise patients of possible hair loss. 
4. Patients should be observed closely for hypersensitivity reactions, 
especially during the first and second infusions.  Insure that 
recommended premedications are given. 
5. Resuscitation equipment and medications to treat hypersensitivity 
reactions should be available during docetaxel administration.  
6. Monitor liver function tests. 
7. Evaluate site regularly for signs of infiltration. 
8. Monitor for symptoms and signs of fluid retention, peripheral 
neuropathy, and cutaneous reactions. 
8.2.12 
References 
1. Docetaxel prescribing information (Aventis). PDR 2000. 
2. Burris HA, Irvin R, Kuhn J, et al. Phase I clinical trial of taxotere 
administered as either a 2-hour or 6-hour intravenous infusion. 
JCO 1993;11:950-58.  
3. Fossella FV, DeVore R, Kerr RN, et al.  Randomized phase III trial 
of docetaxel versus vinorelbine or ifosfamide in patients with 
advanced non-small-cell lung cancer previously treated with 
platinum-containing chemotherapy regimens.  The TAX 320 Non-
Small Cell Lung Cancer Study Group.  J Clin Oncol 2000; 
18:2354-62. 
4. Piccart M.J., Klijn J, Paridaens R, et al.  Corticosteroids 
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 Drug 
Branch for Breast Cancer. JCO 1997;15:3149. 
5. Tomiak, E., Piccart M.J., Kerger, S., et al. Phase I study of 
docetaxel administered as a 1-hour intravenous infusion on a 
weekly basis. JCO 1994;12:1458. 
6 
Hainsworth JD, Burris HA, Erland JB, Thomas M, Greco FA.  
Phase I trial of docetaxel administered by weekly infusion in 
patients with advanced refractory cancer.  J Clin Oncol 1998; 
16:2164-8. 
7. Hainsworth JD, Burris HA, Litchy, S. et al.  Weekly docetaxel in 
the treatment of elderly patients with advanced non-small-cell lung 
cancer: A Minnie Pearl Cancer Research Network phase II trial, 
Cancer 2000;89:328-33. 

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8.3 
Cisplatin (Cis-Diaminedichloroplatinum, CDDP) 
8.3.1 
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. 
8.3.2 
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 further diluted to 0.5 mg/ml with normal saline, 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 further 
diluted with 250 ml or more of 0.45%-0.9% NaCl and 5% dextrose, or 
normal saline.   
8.3.3 
Administration 
Intravenous over 1-2 hours (see treatment plan) 
8.3.4 
Mechanism of Action 
The mechanism of action of cisplatin has not been clearly elucidated. 
However, preliminary 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. 
8.3.5 
Toxicology 
The major effects in humans have been renal toxicity manifested by 
BUN and serum creatinine elevation, tinnitus and audiologic 
impairment in the high frequency range (4000 to 8000 Hz), nausea 
and vomiting, hyperuricemia, mild to moderate anemia, peripheral 
neuropathy, and electrolyte abnormalities. 
8.3.6 
Incompatibilities 
Cisplatin may react with aluminum which is found in some syringe 
needles or IV sets forming a black precipitate. Cisplatin is less stable 
in solutions that do not contain chloride ions (e.g. 5% dextrose). 
8.3.7 
Availability 
Commercially available. 
8.3.8 
Side Effects 
Hematologic: 
Leukopenia and thrombocytopenia occur, but are 
rarely dose-limiting; anemia. 
Dermatologic: 
Alopecia (uncommon) 
Gastrointestinal: Nausea and vomiting are common. Anorexia, 
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Renal: 
Nephrotoxicity is dose-related and relatively 
uncommon with adequate hydration and diuresis; 
elevated serum creatinine and BUN. 
Hepatic: 
Elevated SGOT and SGPT (AST and ALT). 
Neurologic: 
Peripheral neuropathy (paresthesias) common and 
dose-limiting when the cumulative Cisplatin dose 
exceeds 400 mg/m2; seizures (rare); ototoxicity 
manifested initially by high frequency hearing loss; 
vestibular toxicity (dizziness) uncommon; tetany 
(caused by hypomagnesemia); Lhermitte's sign 
(rare). 
Other: 
Hypomagnesemia, hypocalcemia, hyponatremia, 
vein irritation, papilledema, retrobulbar neuritis 
(rare), anaphylaxis (rare), fatigue, secondary 
AML/MDS (risk is uncommon, but maybe increased 
when given in combination with an anthracycline, 
especially if one or both drugs are given at higher 
than standard doses); secondary tumors (rare). 
Taste changes, tinnitus. 
8.4 
5-Fluorouracil 
8.4.1 
Other names 
5-Fluorouracil, 5-FU, Adrucil, Efudex 
8.4.2 
Classification 
Antimetabolite 
8.4.3 
Mode of Action 
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid 
biosynthesis. The deoxyribonucleotide of the drug inhibits thymidylate 
synthetase, thus inhibiting the formation of thymidylic acid from 
deoxyuridylic acid, thus interfering in the synthesis of DNA. It also 
inter-feres with RNA synthesis. 
8.4.4 
Storage and Stability  
Stable for prolonged periods of time at room temperature if protected 
from light. Inspect for precipitate; if apparent, agitate vial vigorously or 
gently heat to not greater than 140F in a water bath. Do not allow to 
freeze. 
8.4.5 
Administration 
The drug may be given IV push, IV continuous infusion, arterial 
infusion, intracavitary, intraperitoneally, topically, or orally mixed in 
water, grape juice, carbonated beverage. 
8.4.6 
Incompatibilities 
Incompatible with doxorubicin and other anthracyclines. When giving 
doxorubicin IV push or through a running IV, flush line before giving 

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fluorouracil. May form precipitate with fluorouracil in some 
concentrations. 
8.4.7 
Availability 
Commercially available. 
8.4.8 
Side Effects 
Hematologic: 
Leukopenia, thrombocytopenia, anemia; can be 
dose- limiting; less common with continuous 
infusion. 
Dermatologic: 
Dermatitis, nail changes, hyperpigmentation, hand- 
foot syndrome with protracted infusions, alopecia. 
Gastrointestinal: Nausea, vomiting, anorexia; diarrhea, can be dose- 
limiting; mucositis, more common with 5-day 
infusion, occasionally dose- limiting; severe, 
cholera-like diarrhea which can be fatal when given 
with leucovorin. 
Neurologic: 
Cerebellar syndrome (headache and cerebellar 
ataxia). 
Cardiac: 
Angina, noted with continuous infusion. 
Ophthalmic: 
Eye irritation, nasal discharge, watering of eyes, 
blurred vision. 
Hepatic: 
Hepatitis with hepatic infusion. 
8.4.9 
Nursing Implications 
1. Monitor CBC, platelet counts. 
2. Administer antiemetics as indicated. 
3. Monitor for diarrhea. Encourage fluids and treat symptomatically - 
may be dose-limiting. 
4. Assess for stomatitis - oral care recommendations as indicated. 
5. Monitor for neurologic symptoms (headache, ataxia). 
6. Patients on continuous infusions may need instruction regarding 
central IV catheters and portable IV or IA infusion devices. 
7. Inform patient of potential alopecia. 
8.4.10 
References 
Hansen R, Quebbeman E, Ausman R, et al. Continuous systemic 5-
fluorouracil in advanced colorectal cancer: Results in 91 patients. J 
Surg Oncol 40:177-181, 1989. 
Freeman NJ, Costanza ME. 5-Fluorouracil-associated cardiotoxicity. 
Cancer 61:36-45, 1988. ECOG 2/91 
8.5 
Carboplatin 
8.5.1 
Other Names 
CBDCA, Paraplatin, JM-8, NSC-241240 

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8.5.2 
Classification 
Second-generation tetravalent organic platinum compound 
8.5.3 
Mode of Action 
Like cisplatin, carboplatin binds to DNA, thereby inhibiting DNA 
synthesis, in a cell cycle nonspecific manner.  Carboplatin must first 
undergo activation to produce antineoplastic activity.  Bidentate 
carboxylate ligands of carboplatin are displaced by water forming 
(aquation) positively charged platinum complexes which bind to 
nucleophilic sites in DNA, such as the O-6 position on guanine.  
Carboplatin produces predominantly interstrand DNA crosslinks rather 
than DNA-protein crosslinks. Intrastrand crosslinks result from the 
formation of adducts between the activated platinum complexes of the 
drug and the N-7 atom (not exclusively) atom on guanine to produce 
1,2 intrastrand links between adjacent guanine molecules, between 
neighboring guanine and adenosine molecules, or between 
neighboring guanine molecules.  Interstrand cross-linking within the 
DNA helix also occurs.  Platinum adducts may inhibit DNA replication, 
transcription and ultimately cell division. 
8.5.4 
Storage and Stability 
Intact vials are stored at room temperature protected from light. The 
reconstituted solution is stable for at least 24 hours. When further 
diluted in glass or polyvinyl plastic to a concentration of 10mg/mL with 
normal saline or 5% dextrose carboplatin is stable for 8 hours at 25 
degrees C.  Stability with further dilution to 0.5mg/mL has been 
reported for up to 8 hours.  Other stability data indicate that 
carboplatin is stable for up to 24 hours and may be refrigerated, 
however, the manufacturer recommends that reconstituted solutions 
be discarded after 8 hours due to the lack of preservative in drug 
formulation. 
8.5.5 
Dose Specifics 
Carboplatin will be given by IV at an area under the curve (AUC) dose 
of 6. Routine premedication should include at least a 5-HT antagonist 
and dexamethasone. The dose of carboplatin based on target AUC is 
calculated using the Calvert equation: 
Dose (total mg) = Target AUC X (GFR + 25). The patient’s creatinine 
clearance (GFR) in mL/minute is calculated by the Cockgraft Gault 
equation. 
NOTE: 
When using the Calvert equation, GFR should not exceed 
125 mL/min. Thus, the maximum carboplatin dose is 6 x 
(125 + 25), or 900 mg. 
8.5.6 
Preparation 
Add 5, 15, or 45 mL sterile water, normal saline, or 5% dextrose to the 
50, 150, or 450 mg vial, respectively. The resulting solution contains 
10 mg/mL. The desired dose is further diluted, usually in 5% dextrose. 
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8.5.7 
Administration 
Infuse over 30 minutes. 
8.5.8 
Incompatibilities 
Aluminum displaces platinum from the carboplatin molecule, resulting 
in the formation of a black precipitate and loss of potency.  
Carboplatin solutions should not be prepared or administered with 
needles, syringes, catheters, or IV administration sets containing 
aluminum parts that might be in contact with the drug. 
8.5.9 
Drug Interactions 
Concomitant myelosuppressive drugs or radiation therapy may 
potentiate the hematologic toxicity of carboplatin. 
Concomitant nephrotoxic drugs may potentiate the nephrotoxicity of 
carboplatin, particularly when carboplatin is given in high-dose 
chemotherapy regimens. 
8.5.10 
Compatibilities 
Carboplatin (0.3 mg/mL) and etoposide (0.4 mg/mL) are chemically 
compatible in normal saline or 5% dextrose for 24 hours at room 
temperature. 
8.5.11 
Availability 
Commercially available as a lyophilized powder in 50, 150, or 450 mg 
vials. 
8.5.12 
Side Effects 
Hematologic: 
Thrombocytopenia (dose limiting), neutropenia, 
leukopenia, anemia. 
GI: 
Nausea and vomiting (frequent but less severe than 
with cisplatin), treatable with appropriate antiemetic 
prophylaxis. Anorexia, diarrhea and constipation 
have also been reported. 
Dermatologic: 
Rash, urticaria. Rarer reactions include alopecia, 
mucositis, and hypersensitivity reactions. 
Hepatic: 
Abnormal liver function tests, usually reversible with 
standard doses. 
Neurologic: 
Rarely peripheral neuropathy is seen. May be more 
common in patients greater than 65 years of age. 
May also be cumulative, especially in patients with 
prior cisplatin treatment. Ototoxicity (rare). 
Renal: 
Elevations in serum creatinine, BUN; electrolyte 
loss (Mg, K, Na, Ca). 
Miscellaneous: 
Pain, asthenia, flu-like syndrome. 

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8.5.13 
Nursing Implications 
1. Monitor CBC and platelet count routinely. 
2. Premedicate with antiemetics – prophylaxis with a 5HT3 receptor 
antagonist and dexamethasone (+/- aprepitant) is standard. 
3. Monitor fluid status – maintain adequate hydration. 
4. Assess skin/mucous membranes. 
5. Assess for signs of peripheral neuropathy – coordination, sensory 
and hearing loss. 
8.5.14 
References 
1. American Hospital Formulary Service 2003-Drug Information. 
2. Calvert AH, et al. Carboplatin dosage: Prospective evaluation of a 
simple formula based on renal function. J Clin Oncol 7: 1748-56, 
1989. 
3. Carboplatin package insert, Princeton, NJ; Bristol Laboratories 
Oncology Products 1998; June 
4. Christian MC. Carboplatin. In: Principles and Practice of 
Oncology, PPO Updates 3(11): 1-16, 1989. 
5. Woloschuk DMM, Pruemer JM, Cluxton RJ. Carboplatin: A new 
cisplatin analog. Drug Intell Clin Pharm 22;843-9, 1988. 
Date/Reviewer: May 2003/Chris Fausel, Pharm.D. 

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9. 
Statistical Considerations 
9.1 
Objectives 
The primary goal of this phase III study is to determine if bevacizumab combined  
with one of four standard platinum doublets improves overall survival compared  
to the doublets alone in patients with recurrent or metastatic head and neck 
cancer. Secondary endpoints include the assessment of toxicities, objective 
response rates, progression-free survival, and the impact of comorbidities on 
these endpoints.  In addition, tumor and blood samples will be collected from the 
patients enrolled in study and studies using these samples will be performed and 
correlated with outcome parameters. Overall survival is defined as the time from 
randomization to date of death from any cause, censored at date of last contact.  
9.2 
Randomization 
Randomization will be done using permuted blocks within strata, with dynamic 
balancing within main institutions and their affiliate networks. This will be an 
intention to treat analysis based on all randomized patients. Patients will be 
equally randomized to the two arms: Arm A - platinum doublet alone or Arm B - 
platinum doublet plus bevacizumab.  Randomization will be stratified by choice of 
chemotherapy combination (cisplatin/docetaxel vs carboplatin/ docetaxel vs 
cisplatin/5-FU vs carboplatin/5-FU), performance status (0 vs 1), weight loss in 
the last 6 months (< 5% vs ≥ 5%), and prior radiation of the head and neck (yes 
vs. no). The sample size calculation will be based on the primary endpoint, 
overall survival. 
9.3 
Accrual 
The study hypothesis is that the addition of bevacizumab will improve the median 
survival by 35% from 8.5 months (based on E1395 and E5397) to 11.5 months.  
Allowing for the interim analysis plan described below, accrual of 400 total 
patients and a total information of 354 deaths will be needed to obtain 80% 
power to detect a 26% reduction in the hazard rate with 0.025 type I error, which 
corresponds to a 35% improvement in median survival assuming exponential 
distributions.  Assuming an accrual rate of 10 patients per month (based on 
E1302), patients will be accrued over 40 months and followed for an additional 
15.5 months, for a total study duration of approximately 4.6 years (55.5 months).  
9.4 
Data monitoring and early stopping rules 
Interim analyses comparing overall survival between the two arms using log-rank 
tests will be performed for all semi-annual DMC meetings beginning when 25% 
of the planned full information (89 deaths) has occurred, approximately 19.5 
months after the study opens, and continuing until either criteria for early 
stopping are met or full information is reached. The trial will be monitored 
according to principles of group-sequential methods using a one-sided O'Brien-
Fleming upper boundary in order to preserve the overall type I error rate of 0.025.  
At each analysis, critical values for the log-rank test will be calculated using a 
truncated Lan-Demets error spending rate function corresponding to the O’Brien-
Fleming boundary.   
The study will also be monitored for early stopping in favor of the null hypothesis 
using Jennison-Turnbull repeated confidence interval (RCI) methodology. At 
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each interim analysis, the RCI for the hazard ratio will be calculated using the 
critical value from the O’Brien Fleming boundary. The ECOG-ACRIN DMC may 
consider stopping the trial in favor of the null hypothesis for lack of benefit if the 
RCI does not include the target alternative hazard ratio of 1.35.   
9.5 
Early Stopping for Excessive Toxicity 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies.  Expedited reporting of certain adverse events is required.  Due to the 
potentially high rate of fatal vascular hemorrhagic episodes, the rates of grade 3-
5 bleeding events will be monitored continuously and the difference between the 
treatment arms will be assessed after every 100 patients are enrolled on the trial 
(50 per arm).  A true rate of grade 5 bleeding events of 1-2% would be 
considered acceptable and is expected.  One-sided Fisher’s exact tests with 
alpha of 0.05 will be used at each interim analysis, and no adjustments will be 
made for multiple comparisons. Suspension of the trial will be considered if there 
is a significant difference between the arms. The following table shows the power 
for detecting a difference in grade 5 bleeding events of 1% on Arm A versus 6%, 
8% or 10% on Arm B for each interim analysis. 
 
Power (%) 
Difference in Arm A vs Arm B 
Sample size per arm 
1% vs 6% 
1% vs 8% 
1% vs 10% 
50 
11 
25 
42 
100 
44 
68 
84 
150 
68 
88 
96 
200 
83 
96 
99 
9.6 
Gender and Ethnicity  
Based on previous data from E1395, the anticipated accrual in subgroups 
defined by gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
27 
27 
Not Hispanic or Latino 
82 
291 
373 
Ethnic Category: Total of all subjects 
82 
318 
400 
Racial Category 
American Indian or Alaskan Native 
2 
0 
2 
Asian 
0 
4 
4 
Black or African American 
4 
45 
49 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
76 
269 
345 
Racial Category: Total of all subjects 
82 
318 
400 
The accrual targets in individual cells are not large enough for definitive 
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accrual to the study will not be extended to meet individual subgroup accrual 
targets. 
9.7 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting.  These group meeting 
reports are made available to the local investigators, who may provide them to 
their IRBs. Only the study statistician and the DMC members will have access to 
interim analyses of outcome data. Prior to completion of this study, any use of 
outcome data will require approval of the DMC. Any DMC recommendations for 
changes to this study will be circulated to the local investigators in the form of 
addenda to this protocol document. A complete copy of the ECOG-ACRIN DMC 
Policy can be obtained from the ECOG-ACRIN Operations Office – Boston. 
 

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10. 
Correlative Studies 
Unless a patient has opted out of providing tumor/blood for correlative studies, the 
investigator must submit the required diagnostic tumor blocks, blood, and frozen tissue 
(if available) as specified below. 
We propose a comprehensive approach to predict bevacizumab efficacy and toxicity, as 
well as to explore the molecular biology and sex differences of head and neck cancer. 
Subjects will have DNA, RNA, plasma, serum, whole blood and tissue collected. An 
initial panel of biomarkers, described briefly below, is planned and additional markers will 
be added as they are identified. 
10.1 
Sample Submissions 
Kits for sample collection and shipment are available for sites in the United 
States and Canada. Complete the KIT ORDER FORM (Appendix V) and fax to 
Zemotak-International at (800) 815-4675. 
All specimens submitted must be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). See Section 10.1.5. 
NOTE: 
Institutions outside the United States and Canada are not required to 
participate in the fresh tissue (peripheral blood) studies because of 
the costs and problems associated with international shipping.   
10.1.1 
Sample schedule 
NOTE: 
Blood samples are to be drawn in the order listed. 
 
Pre-study 
Cycle 2, Day 1 
Paraffin embedded tumor 1 
X 
 
Serum (one 10 mL red top tube)   
X 
X 
Plasma (two 10 mL EDTA purple top 
tubes)   
X 
X 
Peripheral blood (one 10 mL EDTA purple 
top tube)   
X 
X 
Peripheral blood (PAXgene DNA tube)  
X 
 
Peripheral blood (PAXgene RNA tube)  
X 
X 
1 
Submit with STS generated shipping manifest, pathology reports and 
immunological reports 
 
Shipment Schedule 
• 
The EDTA peripheral blood is to be shipped at ambient 
(or cool pack) the day of collection.   
• 
Tissue blocks are submitted at ambient within one month 
of randomization.   
• 
Serum, plasma: If ≤ -70°C freezer available, store 
specimens and batch ship quarterly on dry ice.  Otherwise, 
store at -20°C  until frozen and ship on dry ice/frozen cool 
pack in a split shipper with the EDTA peripheral blood. 
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• 
PAXgene DNA and PAXgene RNA: May be shipped at 
ambient with the EDTA peripheral blood, or frozen with the 
serum and plasma. 
Questions about sample collection or submission are to be directed to 
the ECOG-ACRIN Central Biorepository and Pathology 
Facility(CBPF), Tel: 844-744-2420. 
10.1.2 
Sample Preparation Guidelines 
Samples must be labeled with the protocol number, ECOG-ACRIN 
patient sequence number, date AND time of collection, and sample 
type (serum, plasma, etc.) 
10.1.2.1 
Tissue Samples 
When a patient is randomized to receive protocol therapy, 
the submitting pathologist and clinical research associate 
should refer to Appendix II (Pathology Submission 
Guidelines). 
Required materials 
A. 
Forms: 
• Copy of the surgical pathology report. 
• Reports of immunologic studies, if performed   
B. 
Biological Material Submission: 
• Diagnostic tumor tissue block  
NOTE: 
If a block is unavailable for submission, 
contact the ECOG-ACRIN CBPF (844-
744-2420) to obtain description of 
alternative submission requirements. 
10.1.2.2 
Blood Samples 
Peripheral blood samples are to be drawn in the following 
order: red top tube, green top tubes, purple top tubes, 
Monday through Thursday only. Ideally, blood for the 
serum and plasma specimens should be processed within 
2 hours from the time the blood is drawn and must be 
frozen within 4 hours of the blood draw.  Ideally, serum and 
plasma should be frozen in ultra-cold freezer (<-70°C or 
colder). The faster the blood can be processed from the 
time of the blood draw to freezing, the better. 
A. 
Serum (no anticoagulant, e.g. SST or red top) 
1. Draw a minimum of 10 mL into the vacutainer. 
2. Allow the blood to clot upright at room 
temperature for 30 minutes (if longer than 30min, 
store at 4oC in a refrigerator or in a bucket with 
excess wet ice for no longer than 3 hrs from the 
time of the blood draw). 
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3. Centrifuge the blood at ~ 3,500 rpm at 4oC for 10 
min to separate the serum (clear liquid with straw 
color found in top layer). If the ideal equipment is 
not available, the minimum requirements are 
3,000 rpm (~1000 x g) at room temperature for 15 
minutes.  
4. Draw the serum into a sterile syringe (or a 
transfer pipette) and then evenly dispense 
(aliquot) into the labeled cryotubes in 2 mL 
aliquots. Cap the vials securely. Discard cells. 
5. Freeze (≤ -70oC preferred), in an upright position 
if possible, until shipped. 
B. 
Plasma – EDTA (purple top tube) 
1. Draw a minimum of 15-20 mL blood into two 
10mL EDTA purple top tubes. Mix the blood with 
the additive by gently inverting the tube 5-10 
times.  To avoid hemolysis, do not mix vigorously.   
2. Centrifuge the blood within 30 minutes of blood 
draw.  If the blood cannot be centrifuged right 
away, protect it from light by wrapping the tube in 
foil and storing upright in a refrigerator or a 
bucket of ice.  
Centrifuge the blood at ~3,500 rpm at 4oC for 10 
min.  If the ideal equipment is not available, the 
minimum requirements are 3,000 rpm (~1000 x g) 
at room temperature for 15 min.  Avoid 
centrifugations without refrigeration longer than 
15 min. as excess heat may build up in the unit 
and damage the plasma. 
3. Withdraw the plasma from the vacutainers and 
place into two sterile cryotubes.  Centrifuge the 
plasma a second time as described above. 
4. Carefully draw the plasma into a sterile syringe 
(or a transfer pipette) and then dispense (aliquot) 
into the labeled cryotubes as follows: 
• 
Four (4) 1 mL aliquots 
• 
Remainder into one (1) 10 mL cryovial 
• 
Securely cap the cryogenic vials. 
5. Freeze (≤ -70oC preferred), in an upright position 
if possible, until shipped. 
C. 
Peripheral Blood – EDTA (purple top tube) 
Peripheral blood samples are to be collected Monday 
through Thursday only. 
1. Draw blood into one 10 mL vacutainer.  
2. Invert gently eight to ten times to thoroughly mix 
the blood and anti-coagulant. 

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3. Ship at ambient temperature the day of collection. 
D. 
Peripheral Blood – PAXgene DNA and RNA tubes 
NOTE: 
Samples may be collected Sunday 
through Saturday 
1. Draw blood into one DNA PAXgene (baseline 
only) and one RNA PAXgene tube.  Invert gently 
eight to ten times to thoroughly mix the blood and 
anti-coagulant. 
2. Samples may be stored as follows: 
a. Ambient temperature if shipped day of 
collection or at 2°C to 8°C for 4 days.  Ship 
with EDTA peripheral blood.  
b. Freeze and ship the blood, within the 
PAXgene vacutainer tubes, with the serum 
and plasma specimens. 
10.1.3 
Shipping Guidelines 
Materials shipped overnight must be shipped SUNDAY THROUGH 
THURSDAY only. Do not ship samples the day before a Holiday.  To 
obtain the overnight courier account number contact ECOG-ACRIN 
CBPF, Tel: 844-744-2420. 
A shipping manifest generated from the ECOG-ACRIN STS must 
accompany all submissions. 
Submission Schedule 
Ship Monday through Thursday only. Multiple patient samples may be 
batch shipped together. 
1. Tissue blocks must be submitted at ambient temperature within 1 
month of patient randomization. If on hand, samples may be 
shipped with the baseline peripheral blood sample (package 
appropriately). 
2. Peripheral blood collected in the EDTA tubes are to be shipped 
overnight at ambient temperature (on cool pack or wet ice during 
warm months, package must be leak-proofed) the day of 
collection. 
3. PAXgene tubes may be shipped at ambient with the EDTA 
peripheral blood, or frozen with the serum and plasma. 
4. Serum, and plasma are to be shipped overnight on dry ice or 
frozen kool packs. Ship on a quarterly basis if stored at ≤ -70oC. 
Otherwise ship via a combination (ambient/frozen) shipment  
Combination Shipment: Shipping Both Frozen and Ambient 
Samples Together. 
• 
Line the styrofoam containers with enough absorbent material to 
absorb any contents that may leak.   
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• 
Each frozen sample must be in its own cryovial or sealed 
container. The frozen samples are then placed into a biohazard 
bag, sealed and placed into the large styrofoam container.  
• 
Add DRY-ICE or Frozen Brick into large styrofoam. Use enough of 
DRY ICE to last 4 days. Cover the Styrofoam. 
• 
Place room temp samples (Paxgene, EDTA peripheral blood) into 
small styrofoam/cardboards provided. Fixed tissue blocks may be 
submitted with these samples. 
• 
Place the styrofoam containers into large cardboard box. 
• 
Affix IATA labels (UN3373, Biohazard, and DRY-ICE label if dry-
ice is used) on the cardboard box. Sites outside of US borders 
must include CDCP permit label on shipment. 
• 
Place documents (STS Shipping manifest or Material Submission 
Form) on top, then seal box.  
Ship to the ECOG-ACRIN CBPF: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
10.1.4 
Central Laboratory: Sample Processing and Routing 
The ECOG-ACRIN CBPF will process samples and distribute the 
appropriate materials to investigators for the correlative studies as 
defined below.  Specimens will be processed to maximize their utility 
for the defined and future research, and may include, but not be 
limited to, the extraction of proteins, RNA, and DNA and the 
generation of tissue microarrays (TMAs). 
10.1.5 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples 
submitted on this trial be entered and tracked using the ECOG-ACRIN 
Sample Tracking System (STS). The software will allow the use of 
either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and 
password.   
When you are ready to log the collection and/or shipment of the 
samples required for this study, please access the Sample Tracking 
System software by clicking https://webapps.ecog.org/Tst.  
Important: Additionally, please note that the STS software creates 
pop-up windows, so you will need to enable pop-ups 
within your web browser while using the software.  A 
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user manual and interactive demo are available by 
clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a 
moment to familiarize yourself with the software prior to 
using the system. 
An STS generated shipping manifest must be shipped with all 
specimen submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog-acrin.tst@jimmy.harvard.edu. 
Study Specific Notes 
If the STS is unavailable, the Generic Specimen Submission Form 
(#2981) is to be used as a substitute for the STS shipping manifest. 
The completed form is to be faxed to the receiving laboratory the day 
the samples are shipped. Indicate the appropriate Lab on the 
submission form: 
• 
ECOG-ACRIN CBPF 
Retroactively enter all specimen collection and shipping information 
when STS is available. 
10.2 
 
 
 
 
10.3 
Biomarkers to Predict Chemotherapy and Bevacizumab Toxicity  
Baseline samples in all participating subjects will be analyzed to assess common 
SNPS associated with chemotherapy drug metabolism, thrombosis, and 
bleeding. This data will be evaluated to predict toxicity associated with 
chemotherapy and bevacizumab. 
10.4 
Banking  
Residual material from the samples submitted and analyzed by the designated 
laboratories will be forwarded to and retained at the ECOG-ACRIN Central 
Repository for possible use in future ECOG-ACRIN approved studies. Any 
residual blocks will be available for purposes of individual patient management 
on specific written request. If future use is denied or withdrawn by the patient, the 
samples will be removed from consideration for use in any future study. 
10.5 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted and used on the above-mentioned 
laboratory correlative study(ies) will be submitted to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis. Inventories will be submitted, 
electronically or by diskette by any laboratory holding and/or using any 
specimens associated with this study, to ecog.labdata@jimmy.harvard.edu. All 
other correspondence should be addressed to the attention of the Translational 
Science Team. 
Rev. 1/15 
Redacted

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10.6 
Lab Data Transfer Guidelines  
The data collected on the above mentioned correlative study(ies) will be 
submitted to the ECOG-ACRIN Operations Office – Boston by the central 
laboratory(ies) on a quarterly basis. The quarterly cut-off dates are March 31, 
June 30, September 30, and December 31. Data is due at the ECOG-ACRIN 
Operations Office – Boston 1 week after these cut-off dates. Electronic 
submissions should be submitted to ecog.labdata@jimmy.harvard.edu. All other 
correspondence should be addressed to the attention of the Translational 
Science Team. 
 

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11. 
Records to Be Kept 
Please refer to the E1305 Forms Packet for the forms submission schedule and copies 
of all forms. The E1305 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office – Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study may be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication 
being studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
• 
Please contact the ECOG-ACRIN Operations Office – Boston prior to 
destroying any source documents. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
1. 
Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 
2005;55(1):10-30. 
2. 
Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin 
plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced 
squamous-cell carcinoma of the head and neck: a Southwest Oncology Group 
study. Journal of Clinical Oncology 1992;10(8):1245-51. 
3. 
Gibson MK, Li Y, Murphy B, et al. Randomized phase III evaluation of cisplatin plus 
fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer 
(E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin 
Oncol 2005;23(15):3562-7. 
4. 
Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study 
comparing cisplatin and fluorouracil as single agents and in combination for 
advanced squamous cell carcinoma of the head and neck. J Clin Oncol 
1992;10(2):257-63. 

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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
105 
5. 
Morton RP, Rugman F, Dorman EB, et al. Cisplatinum and bleomycin for advanced 
or recurrent squamous cell carcinoma of the head and neck: a randomised factorial 
phase III controlled trial. Cancer Chemother Pharmacol 1985;15(3):283-9. 
6. 
Forastiere AA, Shank D, Neuberg D, Taylor SGt, DeConti RC, Adams G. Final 
report of a phase II evaluation of paclitaxel in patients with advanced squamous 
cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group trial 
(PA390). Cancer 1998;82(11):2270-4. 
7. 
Vermorken JB, Catimel G, Mulder PD, et al. Randomized Phase II Trial of Weekly 
Methotrexate (MTX) Versus Two Schedules of Triweekly Paclitaxel (Taxol[trade]) 
in Patients with Metastatic or Recurrent Squamous Cell Carcinoma of the Head 
and Neck (SCCHN). Proc Am Soc Clin Oncol 1999;18:A1527. 
8. 
Burtness BA, Li Y, Flood W, Mattar BI, Forastiere AA. Phase III trial comparing 
cisplatin (C) + placebo (P) to C + anti-epidermal growth factor antibody (EGF-R) 
C225 in patients (pts) with metastatic/recurrent head & neck cancer (HNC). Proc 
Am Soc Clin Oncol 2002;21:A901. 
9. 
Glisson BS, Murphy BA, Frenette G, Khuri FR, Forastiere AA. Phase II Trial of 
docetaxel and cisplatin combination chemotherapy in patients with squamous cell 
carcinoma of the head and neck. J Clin Oncol 2002;20(6):1593-9. 
10. Schoffski P, Catimel G, Planting AS, et al. Docetaxel and cisplatin: an active 
regimen in patients with locally advanced, recurrent or metastatic squamous cell 
carcinoma of the head and neck. Results of a phase II study of the EORTC Early 
Clinical Studies Group. Ann Oncol 1999;10(1):119-22. 
11. Specht L, Larsen SK, Hansen HS. Phase II study of docetaxel and cisplatin in 
patients with recurrent or disseminated squamous-cell carcinoma of the head and 
neck. Ann Oncol 2000;11(7):845-9. 
12. Shemirani B, Crowe DL. Head and neck squamous cell carcinoma lines produce 
biologically active angiogenic factors. Oral Oncol 2000;36(1):61-6. 
13. Riedel F, Gotte K, Schwalb J, Schafer C, Hormann K. Vascular endothelial growth 
factor expression correlates with p53 mutation and angiogenesis in squamous cell 
carcinoma of the head and neck. Acta Otolaryngol 2000;120(1):105-11. 
14. DeFatta RJ, Nathan CA, De Benedetti A. Antisense RNA to eIF4E suppresses 
oncogenic properties of a head and neck squamous cell carcinoma cell line. 
Laryngoscope 2000;110(6):928-33. 
15. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, 
fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 
2004;350(23):2335-42. 
16. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves 
survival when combined with FOLFOX4 in previously treated advanced colorectal 
cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study 
E3200. Proc Am Soc Clin Oncol 2005:A2. 
17. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III Trial of paclitaxel 
(P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients 
with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern 
Cooperative Oncology Group (ECOG) Trial - E4599. Proc Am Soc Clin Oncol 
2005:LBA4. 
18. Miller KD, Wang M, Gralow J, et al. E2100. A randomized phase III trial of 
paclitaxel versus paclitaxel plus bevacizumab as first-line therapy of locally 
recurrent or metastatic breast cancer. In: Annual ASCO meeting; 2005; 2005. 

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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
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19. Vokes EE, Cohen EE, Mauer AM, et al. A phase I study of erlotinib and 
bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and 
neck (HNC). Proc Am Soc Clin Oncol 2005:A5504. 
20. Mauer AM, Cohen EEW, Wong SJ, et al. Phase I study of epidermal growth factor 
receptor (EGFR) inhibitor, erlotinib, and vascular endothelial growth factor 
monoclonal antibody, bevacizumab, in recurrent and/or metastatic squamous cell 
carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 
2004;23:A5539. 
21. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular 
endothelial growth factor monoclonal antibody for the therapy of solid tumors and 
other disorders. Cancer Res 1997;57(20):4593-9. 
22. Avastin™ (bevacizumab) Investigator’s Brochure, 11th version, December 2004. 
23. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced 
angiogenesis suppresses tumour growth in vivo. Nature 1993;362(6423):841-4. 
24. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 
2004;10(2):145-7. 
25. Kabbinavar FF, Wong JT, Ayala RE, al e. The effect of antibody to vascular 
endothelial growth factor and cisplatin on the growth of lung tumors in nude mice. 
In: Annual Meeting of the American Association for Cancer Research; 1995; 1995. 
26. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of 
targeting both pericytes and endothelial cells in the tumor vasculature with kinase 
inhibitors. J Clin Invest 2003;111(9):1287-95. 
27. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer 
carcinomatosis by antibodies to vascular endothelial and epidermal growth factor 
receptors. Br J Cancer 2001;85(4):584-9. 
28. Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of 
bevacizumab in previously treated metastatic breast cancer. Semin Oncol 
2003;30(5 Suppl 16):117-24. 
29. Miller K, H.S. Rugo, M.A. Cobleigh, et al. Phase III trial of capecitabine(Xeloda) 
plus bevacizumab(Avastin) versus capecitabine alone in women with metastatic 
breast cancer(MBC)previously treated with an anthracycline and a taxane. Breast 
Cancer Res Treat 2002;76:S37. 
30. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-
vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J 
Med 2003;349(5):427-34. 
31. Novotny WF, Holmgren E, Griffing S, Johnson D, De Vore R, Kabbinavar FF. 
Identification of Squamous Cell Histology and Central, Cavitary Tumors as 
Possible Risk Factors for Pulmonary Hemorrhage in Patients with Advanced 
NSCLC Receiving Bevacizumab. Proc Am Soc Clin Oncol 2001:A1318. 
32. Skillings JR, Johnson DH, Miller K, et al. Arterial thromboembolic events (ATEs) in 
a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) 
with chemotherapy. Proc Am Soc Clin Oncol 2005:A3019. 
 

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with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Update #5] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Update #5 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 
 

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with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. List of Required Materials for E1305 
3. Instructional memo to submitting pathologists 
4.  ECOG-ACRIN Generic Specimen Submission Form (#2981) 
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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
STS generated shipping manifest 
Instructions: 
1. Provide the following information to the pathologist.: 
• 
Patient's name (last, first) 
• 
Protocol number 
• 
Protocol case number (the patient's ECOG-ACRIN sequence number) 
• 
Patient's hospital number 
• 
Institution 
• 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo, and forward it, along 
with the List of Required Material and the Specimen Submission Form, to the 
appropriate pathologist. 
3. The pathologist should return to you the required pathologic samples and surgical 
pathology reports, along with the completed specimen submission form, if requested. 
If any other reports are required, they should be obtained from the appropriate 
department at this time. 
4. Keep a copy of the Specimen Submission Forms or shipping manifests for your 
records. 
5. Double check that ALL required forms, reports, and pathology samples are included 
in the package to send to the Central Biorepository and Pathology Facility (see 
appropriate List of Required Material). 
Pathology specimens submitted for a patient WILL NOT be processed by the 
Central Biorepository and Pathology Facility until all necessary items are 
received. 
6. Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions, or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility at Tel: 844-744-2420  or email: eacbpf@mdanderson.org. 
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List of Required Material 
Protocol #: E1305 
Title: A Phase III Randomized Trial of Chemotherapy with or 
without Bevacizumab In Patients with Recurrent Or 
Metastatic Head and Neck Cancer  
Pre-Treatment 
1. ECOG-ACRIN Generic Specimen Submission Form (#2981) Institutional pathology 
report (must be included with EVERY pathology submission). 
2. Immunological studies, if available. 
3. Required path materials 
A representative paraffin block of the original diagnosis or a repeat biopsy will be 
submitted. If blocks cannot be submitted, 10 unstained slides of 4 micron section 
mounted on positively-charged glass slides are acceptable. 
NOTE: 
Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
 
Rev. 1/15 

 
111 
MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for E1305: A Phase III Randomized 
Trial of Chemotherapy with or without Bevacizumab In Patients with 
Recurrent Or Metastatic Head and Neck Cancer  
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by ______________________________ (ECOG-ACRIN Investigator).  This 
protocol requires the submission of pathology materials for laboratory studies and 
banking for future research. 
Keep a copy of the submission for your own records. Forward the surgical pathology 
report(s), the slides and/or blocks, and any other required material (see attached List of 
Required Material) to the Clinical Research Associate (CRA). The CRA will forward all 
required pathology material to the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies. Paraffin blocks will be returned upon written request for 
purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please feel free to contact the Central 
Biorepository and Pathology Facility at Tel:  844-744-2420  OR email: 
eacbpf@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: __________________________________  
Address: ________________________________  
Phone: __________________________________  
 
Thank you. 
 
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Page 1 of 1 
112 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
 
 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important clinical program.  Programs like this 
offer a chance to get the best care while helping us make better care available for all 
patients. Many questions remain unanswered in cancer. With the participation of people 
like you in clinical trials, we will improve treatment and quality of life for those with your 
type of cancer. 
We believe this program will provide you with high quality, thorough care.  Your 
physician and research staff will maintain very close contact with you.  This is important 
to allow your physician to provide you with the best care while learning as much as 
possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 
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NCI Update Date: November 20, 2013 
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A Phase III Randomized Trial of Chemotherapy with or without Bevacizumab In Patients 
with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix IV 
 
Cancer Trials Support Unit (CTSU) Participation Procedures 
 
[Deleted in Addendum #11] 
 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
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with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix V 
 
E1305 Collection and Shipping Kit Order Form 
NOTE: 
Starter kits are not available. It is preferred that the patient has registered to the trial.  
At a minimum, there must be a signed consent to participate. 
DATE :   
Provide the following information: 
□ E1305 patient case number: 
 
□ Patient not registered, consented only 
Institutional Contact Name: 
 
Phone number for contact: 
 
Fax number for contact: 
 
E-mail for contact: 
 
Kit is to be shipped to: 
 
 
 
 
 
 
 
FAX Completed form to Zemotak-International at (800) 815-4675 
NOTE: Questions are to be directed to the ECOG-ACRIN CBPF, Attn:  Adekunle Raji,  
Phone: Toll Free 844-744-2420 
Email: eacbpf@mdanderson.org 
Comments: 
 
 
 
Rev. 1/15 

ECOG-ACRIN 
E1305 
Cancer Research Group 
Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
116 
A Phase III Randomized Trial of Chemotherapy with or without Bevacizumab In Patients 
with Recurrent Or Metastatic Head and Neck Cancer 
 
Appendix VI 
 
E1305 Shipping Notification Form 
All samples are to be logged and tracked in the ECOG-ACRIN Sample Tracking System. 
If the STS is unavailable, the Generic Specimen Submission Form (#2981) is to be used as a 
substitute for the STS shipping manifest. The completed form is to be faxed to the receiving 
laboratory the day the samples are shipped. Indicate the appropriate Lab on the submission 
form: 
• 
ECOG-ACRIN CBPF 
Retroactively enter all specimen collection and shipping information when STS is available. 
 
Rev. 1/15 

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E1305 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
117 
A Phase III Randomized Trial of Chemotherapy with or without Bevacizumab In Patients 
with Recurrent Or Metastatic Head and Neck Cancer 
Appendix VII 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rev. 8/14 
Redacted

ECOG-ACRIN 
E1305 
Cancer Research Group 
Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
118 
 
 
 
 
  
 
 
 
 
 
 
Rev. 1/15 
Redacted

ECOG-ACRIN 
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Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
119 
A Phase III Randomized Trial of Chemotherapy with or without Bevacizumab In Patients 
with Recurrent Or Metastatic Head and Neck Cancer 
Appendix VIII 
 
ASCO 2006 Antiemetic Guidelines 
Drug regimens for the Prevention of Chemotherapy-Induced Emesis by Emetic Risk Category 
 
Emetic Risk Category (incidence of 
emesis without antiemetics) 
Antiemetic Regimens and Schedules 
 
 
High (> 90%) 
5-HT3 serotonin receptor antagonist: day 1 
Dexamethasone: days 1, 2, 3 
Aprepitant: days 1, 2, 3 
 
 
Moderate (30% to 90%) 
5-HT3 serotonin receptor antagonist: day 1 
Dexamethasone: day 1  
(Aprepitant: days 1, 2, 3)* 
 
 
Low (10% to 30%) 
Dexamethasone: day 1 
 
 
Minimal (< 10%) 
Prescribe as needed (see text for details of agent 
selection) 
 
Abbreviation: 5-HT3, %-hydroxytryptamine-3 
* For patients receiving a combination of an anthracycline and cyclophosphamide. 
Kris, Mark G., et al. American Society of Clinical Oncology Guideline for Antiemetics in 
Oncology: Update 2006. J Clin Oncol 24. © 2006 by American Society of Clinical Oncology. 

ECOG-ACRIN 
E1305 
Cancer Research Group 
Version Date: September 9, 2016 
 
NCI Update Date: November 20, 2013 
120 
A Phase III Randomized Trial of Chemotherapy with or without Bevacizumab In Patients 
with Recurrent Or Metastatic Head and Neck Cancer 
Appendix IX 
 
New York Heart Association (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. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II 
Subjects with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest.  Less than ordinary physical 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to carry on physical 
activity without discomfort.  Symptoms of cardiac insufficiency or of 
the anginal syndrome may be present event at rest.  If any physical 
activity is undertaken, discomfort is increased.