Clinical trial NCT00946712
Conditions: Recurrent Large Cell Lung Carcinoma Recurrent Lung Adenocarcinoma Recurrent Squamous Cell Lung Carcinoma Stage IV Large Cell Lung Carcinoma Stage IV Lung Adenocarcinoma Stage IV Squamous Cell Lung Carcinoma
Sponsor: SWOG Cancer Research Network
Start date: 2009-07-15; Completion date: 2022-02-08
Enrollment: 1333 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies carboplatin and paclitaxel to compare how well they work with or without bevacizumab and/or cetuximab in treating patients with stage IV or non-small cell lung cancer that has returned after a period of improvement (recurrent). Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab may prevent the growth of new blood vessels that tumor needs to grow. Cetuximab may also stop cancer cells from growing by binding and interfering with a protein on the surface of the tumor cell that is needed for tumor growth. It is not yet known whether giving carboplatin and paclitaxel are more effective with or without bevacizumab and/or cetuximab in treating patients with non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare overall survival (OS) in the entire study population. II. To compare progression-free survival (PFS) by institutional review of epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH)-positive patients.

SECONDARY OBJECTIVES:

I. To compare OS and PFS by centralized review in EGFR FISH-positive patients. II. To compare PFS by centralized image review and by institutional review in the entire study population.

III. To compare the response rate (confirmed plus unconfirmed, complete and partial responses) in a subset of patients with measurable disease in EGFR FISH-positive patient and the entire study population.

IV. To assess the toxicities of these treatment regimens. V. To prospectively test EGFR FISH as a predictive marker for the selection of patients for cetuximab plus chemotherapy.

III. To evaluate the role of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in terms of cetuximab efficacy.

IV. To compare the results of EGFR FISH with KRAS mutations, EGFR mutations, EGFR immunohistochemistry (IHC), and other purported EGFR-related biomarkers.

TERTIARY OBJECTIVES:

I. To compare PFS in patients with advanced non-small cell lung cancer (NSCLC) with an IHC score \> 200 treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or without cetuximab.

II. To compare OS in patients with advanced NSCLC with an IHC score \> 200 treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or without cetuximab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.

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

Arms: arm 1: Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes with or without bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients receiving bevacizumab may continue to receive bevacizumab (as above) in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive paclitaxel and carboplatin with or without bevacizumab as in Arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients may continue to receive cetuximab with or without bevacizumab (as above) in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Bevacizumab intervention 2: Carboplatin intervention 3: Cetuximab intervention 4: Laboratory Biomarker Analysis intervention 5: Paclitaxel
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
 
S0819 
 
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Version Date 10/3/16 
 
 
 
 
PRIVILEGED COMMUNICATION 
 
Activated July 15, 2009 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
 
 
SWOG 
 
A RANDOMIZED, PHASE III STUDY COMPARING CARBOPLATIN/PACLITAXEL OR 
CARBOPLATIN/PACLITAXEL/BEVACIZUMAB WITH OR WITHOUT CONCURRENT 
CETUXIMAB IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER 
(NSCLC) 
 
 
PAGE 
SCHEMA ....................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................. 7 
1.1 
Primary Objective ............................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................... 7 
1.3 
Tertiary Objectives ........................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................... 8 
3.0 
DRUG INFORMATION .................................................................................................... 14 
3.1 
Bevacizumab (rhuMAb VEGF) (Avastin) (NSC #704865) ............................................. 14 
3.2 
Carboplatin (CBDCA) (NSC-241240) .............................................................................. 27 
3.3 
Cetuximab (IMC-C225) (Erbitux®) (NSC-714692) ........................................................... 28 
3.4 
Paclitaxel, Taxol® (NSC-673089) ..................................................................................... 36 
4.0 
STAGING CRITERIA ....................................................................................................... 38 
5.0 
ELIGIBILITY CRITERIA .................................................................................................. 40 
5.1 
Disease Related Criteria .................................................................................................. 40 
5.2 
Clinical/Laboratory Criteria ............................................................................................... 42 
5.3 
Regulatory Criteria ........................................................................................................... 43 
6.0 
STRATIFICATION FACTORS ......................................................................................... 44 
6.1 
Bevacizumab–APPROPRIATE Status:  Yes versus No. ................................................. 44 
6.2 
Smoking Status ................................................................................................................ 44 
6.3 
Stage ................................................................................................................................ 44 
7.0 
TREATMENT PLAN ........................................................................................................ 44 
7.1 
Good Medical Practice ..................................................................................................... 44 
7.2 
Pre-medication ................................................................................................................. 45 
7.3 
Treatment ......................................................................................................................... 46 
7.4 
Precautions ...................................................................................................................... 51 
7.5 
Guidelines for Carboplatin Administration ........................................................................ 51 
7.6 
Hematologic Requirements for Day 1 of Each Cycle ....................................................... 52 
7.7 
Supportive Care ............................................................................................................... 52 
7.8 
Criteria for Removal from Protocol Treatment ................................................................. 52 
7.9 
Discontinuation of Treatment ........................................................................................... 52 
7.10 
Follow Up Period .............................................................................................................. 52 
7.11 
Radiology Review ............................................................................................................ 52 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS .......................... 53 
8.1 
NCI Common Terminology Criteria for Adverse Events (CTCAE) ................................... 53 
8.2 
General Dose Modifications ............................................................................................. 53 
8.3 
Dose Modifications for Carboplatin and Paclitaxel .......................................................... 53 
8.4 
Dose Modifications for Cetuximab ................................................................................... 56 
8.5 
Dose Modifications for Bevacizumab ............................................................................... 59 
8.6 
G-CSF Usage ................................................................................................................... 61 
8.7 
G-CSF Dose Modifications............................................................................................... 62 
8.8 
Dose Modifications for Non-Hematologic Toxicity ........................................................... 62 
8.9 
Dose Modification Contacts ............................................................................................. 62 
8.10 
Adverse Event Reporting ................................................................................................. 62 


 
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9.0 
STUDY CALENDAR ........................................................................................................ 62 
9.1 
Study Calendar - ARM 1a - Chemotherapy plus Bevacizumab without Cetuximab ........ 63 
9.2 
ARM 1b - Chemotherapy without Cetuximab................................................................... 65 
9.3 
ARM 2a - Chemotherapy plus Bevacizumab with Cetuximab ......................................... 67 
9.4 
ARM 2b - Chemotherapy with Cetuximab ........................................................................ 70 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS ................................... 73 
10.1 
Measurability of Lesions................................................................................................... 73 
10.2 
Objective Status ............................................................................................................... 73 
10.3 
Best Response ................................................................................................................. 74 
10.4 
Performance Status ......................................................................................................... 75 
10.5 
Progression-Free Survival (Central-Review Based) ........................................................ 75 
10.6 
Progression-Free Survival ............................................................................................... 76 
10.7 
Time to Death ................................................................................................................... 76 
11.0 
STATISTICAL CONSIDERATIONS ................................................................................ 76 
11.1   
Primary Endpoint .............................................................................................................. 76 
11.2   
Secondary Endpoints ....................................................................................................... 76 
11.3  
H-Score ............................................................................................................................ 76 
11.4 
Sample Size With Power Justification .............................................................................. 77 
11.5  
Analysis Plan Including Plans for Formal Interim Analysis .............................................. 77 
11.6  
Amendment to design ...................................................................................................... 80 
11.7 
Accrual Information .......................................................................................................... 81 
11.8 
Data and Safety Monitoring Committee ........................................................................... 82 
12.0 
DISCIPLINE REVIEW ...................................................................................................... 82 
13.0 
REGISTRATION GUIDELINES ....................................................................................... 82 
13.1  
Registration Timing .......................................................................................................... 82 
13.2 
OPEN Registration Requirements ................................................................................... 82 
13.3 
Registration Procedures ................................................................................................... 83 
13.4  
Registration Exceptions ................................................................................................... 84 
14.0 
DATA SUBMISSION SCHEDULE .................................................................................. 84 
14.1 
Data Submission Requirements ...................................................................................... 84 
14.2 
Master Forms ................................................................................................................... 84 
14.3 
Data Submission Procedures .......................................................................................... 85 
14.4 
Data Submission Overview and Timepoints .................................................................... 85 
15.0 
SPECIAL INSTRUCTIONS.............................................................................................. 87 
15.1 
Required Tissue Specimens for EGFR FISH and KRAS ................................................. 87 
15.2 
Required Plasma and Buffy Coat for Translational Medicine and Optional Banking ...... 89 
15.3 
Integral Translational Medicine Studies ........................................................................... 89 
15.4  
Radiology Review ............................................................................................................ 92 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................... 93 
16.1 
Adverse Event Reporting Requirements 
93 
17.0 
BIBLIOGRAPHY .............................................................................................................. 95 
18.0 
APPENDIX ....................................................................................................................... 98 
18.1 
Determination of Expedited Adverse Event Reporting Requirements ............................. 99 
18.2 
Carboplatin Dosing Worksheet ........................................................................................ 101 
18.3 
New York Heart Association Class .................................................................................. 102 
18.4 
Proposed Rash Management Algorithm .......................................................................... 103 
18.5 
Embedded Translational Medicine Studies-Integrated and Other ................................... 104 
18.6 
Central Radiology Review ................................................................................................ 106 
18.7 
Cancer Trials Support Unit (CTSU) Participation Procedures ......................................... 112 
18.8 
SWOG S0819 Pathology Review Form ........................................................................... 116 
 
 
 
 


 
 
 
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STUDY COORDINATORS: 
AGENTS: 
 
 
IND-Exempt Agents: 
Roy S. Herbst, M.D., Ph.D. (Medical Oncology) 
Bevacizumab (rhuMab VEGF) (Avastin)  
Yale Cancer Center 
 
(NSC-704865) 
Section of Medical Oncology 
Carboplatin (CBDCA) (NSC-241240) 
333 Cedar Street, PO Box 208028 
Cetuximab (IMC-C225) (Erbitux®) (NSC-714692) 
New Haven, CT 06520-8028 
Paclitaxel, Taxol® (NSC-673089) 
Phone: 203/785-6879 
 
FAX: 203/785-4116 
 
E-mail: roy.herbst@yale.edu 
 
 
BIOSTATISTICIANS: 
 
Edward S. Kim, M.D. (Medical Oncology) 
Mary Redman, Ph.D.  
Levine Cancer Institute 
James Moon, M.S. 
Carolinas Healthcare System 
SWOG 
1021 Morehead Medical Dr., Suite 3100 
Statistical Center 
Charlotte, NC 28204 
1100 Fairview Ave N, M3-C102 
Phone:  980/442-3105 
PO Box 19024 
FAX:  980/442-3101 
Seattle, WA 98109 
E-mail:  edward.kim@carolinashealthcare.org 
Phone:  206/667-4623 
 
FAX:  206/667-4408 
David R. Gandara, M.D. (Lung Committee Chair) 
E-mail:  mredman@fhcrc.org  
Professor of Medicine  
E-mail:  jmoon@fhcrc.org 
 
UC Davis Cancer Center 
 
4501 X Street, Ste 3017 
ENDORSING GROUPS 
Sacramento, CA 95817 
 
FAX:  916/734-7946 
NCCTG: 
E-mail: david.gandara@ucdmc.ucdavis.edu 
 
 
Alex A. Adjei, M.D., Ph.D. 
Thomas J. Semrad, M.D. (Medical Oncology) 
Roswell Park Cancer Institute 
UC Davis Cancer Center 
 
4501 X Street, Ste 3016 
CALGB: 
Sacramento, CA 95817 
 
Phone:  916/734-3771 
Michael Perry, M.D.  
FAX:  916/734-7946 
University of Missouri/Ellis Fischel Cancer Center 
E-mail:  thomas.semrad@ucdmc.ucdavis.edu 
 
 
 
Fred R. Hirsch, M.D., Ph.D. (Translational Medicine) 
 
University of Colorado CC 
 
PO Box 6511, MS 8117 
 
Aurora, CO 80045  
 
Phone:  303/724-3858 
 
E-mail:  fred.hirsch@ucdenver.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
mb 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 


 
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This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Institutions not aligned with SWOG will participate through the CTSU mechanism as outlined 
below and detailed in the CTSU logistical appendix. 
 
 
The study protocol and all related forms and documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at www.ctsu.org. 
 
 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted.  
 
 
Patient enrollments will be conducted via the OPEN Registration System. Refer to the CTSU 
logistical appendix for specific instructions. 
 
 
Data management will be performed by SWOG. Case report forms (with the exception of patient 
enrollment forms), clinical reports, and transmittals must be sent to SWOG unless otherwise 
directed by the protocol. Do not send study data or case report forms to the CTSU Data 
Operations.  
 
 
Data query and delinquency reports will be sent directly to the enrolling site by SWOG. Please 
send query responses and delinquent data to the SWOG Data Operations Center and do not 
copy the CTSU Data Operations.  
 
 
Each site should have a designated CTSU Administrator and Data Administrator and must keep 
their CTEP IAM account contact information current. This will ensure timely communication 
between the clinical site and the SWOG data center. 
 
 


 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS  
AND CONTACT INFORMATION 
 
To submit site 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 
Please refer to the patient 
enrollment section for 
instructions on using the 
OPEN system. 
 
Online Data Submission:  Institutions 
participating through CTSU are 
required to submit and amend their 
data electronically via Online Data 
submission.  Access the SWOG Work 
bench using your CTSU User ID and 
password at the following url: 
https://crawb.crab.org/TXWB/ctsulogo
n.aspx. 
 
Exceptions:  Data items that are not 
available for online submission 
(operative and pathology reports, 
patient completed forms, scan 
reports, etc.) may be submitted by 
FAX at 800/892-4007.   
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.  
For treatment-related questions contact the Study PI of the Coordinating Group. 
For eligibility or data submission questions contact the SWOG Data Operations Center at 206/652-
2267. 
For questions unrelated to patient eligibility, treatment, or 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.  
The CTSU Public Web site is located at: www.ctsu.org.   
The CTSU Registered Member Web site is located at www.ctsu.org
CTSU logistical information is located in Appendix 18.7 
 


 
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SCHEMA 
 
 
RANDOMIZATION 
 
 
 
 
Arm 1 
Arm 2 
Chemotherapy 
Chemotherapy 
without Cetuximab 
with Cetuximab 
± Bevacizumab 
± Bevacizumab 
 
 
 
 
STRATIFICATION 
 
Bevacizumab-Appropriate 
versus 
Bevacizumab-Inappropriate 
 
 
 
 
 
 
 
 
Arm 1a 
 
Arm 2a 
Carboplatin 
 
Carboplatin 
Paclitaxel 
 
Paclitaxel 
Bevacizumab 
Bevacizumab 
(6 cycles) 
 
Cetuximab 
 
 
(6 cycles) 
 
 
 
 
Bevacizumab 
 
Cetuximab 
 
 
Bevacizumab 
 
OR 
OR 
 
Arm 1b 
Arm 2b 
Carboplatin 
Carboplatin 
Paclitaxel 
Paclitaxel 
(6 cycles) 
Cetuximab 
 
(6 cycles) 
 
 
 
 
 
 
 
 
 
Cetuximab 
 
 
 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
In patients with advanced NSCLC treated with carboplatin, paclitaxel and bevacizumab (if 
appropriate) with or without cetuximab, the primary objective of this study is to compare: 
 
a. 
Overall survival (OS) in the entire study population, 
 
b. 
Progression-free survival (PFS) by institutional review in EGFR FISH-positive 
patients. 
 
1.2 
Secondary Objectives 
 
a. 
In patients with advanced NSCLC treated with carboplatin, paclitaxel and 
bevacizumab (if appropriate) with or without cetuximab, the secondary objectives 
are to compare: 
 
1. 
OS and PFS by centralized review in EGFR FISH-positive patients, 
 
2. 
PFS by centralized image review and by institutional review in the entire 
study population. 
 
b. 
To compare the response rate (confirmed plus unconfirmed, complete and partial 
responses) in the subset of patients with measurable disease in: 
 
1. 
EGFR FISH-positive patient, 
 
2. 
the entire study population. 
 
c. 
To assess the toxicities of these treatment regimens. 
 
d. 
To prospectively test EGFR FISH as a predictive marker for the selection of 
patients for cetuximab plus chemotherapy. 
 
e. 
To evaluate the role of KRAS mutations in terms of cetuximab efficacy. 
 
f. 
To compare the results of EGFR FISH with KRAS mutations, EGFR mutations, 
EGFR IHC and other purported EGFR-related biomarkers. 
 
1.3 
Tertiary Objectives  
 
The tertiary objectives of this study are: 
 
a. 
To compare PFS in patients with advanced NSCLC with an IHC score > 200 
treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or 
without cetuximab, 
 
b. 
To compare OS in patients with advanced NSCLC with an IHC score > 200 
treated with carboplatin, paclitaxel, and bevacizumab (if appropriate) with or 
without cetuximab. 
 
 


 
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2.0 
BACKGROUND 
 
Rationale for selected approach and trial design.  
 
Lung cancer is the most frequent cause of cancer death in the United States, with only 15% of 
patients surviving 5 years after diagnosis.  Poor survival reflects, in part, the fact that almost 50% 
of cases present with advanced stage disease, for which effective systemic therapies are limited.  
However, recent development of novel molecular therapies, such as inhibitors of the epidermal 
growth factor receptor (EGFR), offer considerable promise for patient subsets sensitive to these 
agents.  The EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib were the first molecular 
targeted agents to demonstrate benefit in patients with advanced non-small cell lung cancer 
(NSCLC). Early studies defined patient characteristics of those most likely to respond as: female 
sex, adenocarcinoma or bronchioloalveolar cell carcinoma (BAC) histology, never-smoker and 
Asian.  BR.21, an NCI-Canada trial comparing erlotinib to placebo as 2nd line therapy in unselected 
patients, was the first demonstration of survival benefit for any targeted agent in NSCLC.  A similar 
placebo-controlled study with gefitinib, the ISEL study, did not show a survival benefit, perhaps 
due to differences in patient eligibility criteria.  Even in BR.21, the response rate to erlotinib was < 
10% and the overall impact on survival was modest, prompting research efforts to define 
molecular biomarkers predictive of clinical benefit, especially improved survival.  (1) Although a 
number of potential EGFR biomarkers have been proposed, including EGFR protein expression, 
mutation status, and gene copy number defined by FISH, EGFR FISH was most effective in 
predicting survival benefit in the two placebo-controlled randomized trials:  hazard ratio (HR) for 
EGFR FISH-positive patients of 0.44 in the BR.21 study and 0.61 in ISEL.  (2-4) 
 
The presence of certain EGFR tyrosine kinase domain (TKD) mutations defines an NSCLC patient 
subset in which dramatic responses to EGFR TKIs are often seen, but outside of Asian 
populations, this biomarker is not clearly associated with prolonged survival from EGFR TKI 
therapy.  This discrepancy perhaps reflects the low incidence of these TKD mutations in western 
populations of NSCLC. For example, there was no improvement in survival in patients with EGFR 
mutations in the BR.21 trial, despite an association with improved response rates.  (2-3)  In terms 
of prognosis, i.e., independent of therapy, studies performed to date suggest that EGFR mutations 
are actually associated with a good prognosis and more indolent course. In the TRIBUTE study of 
chemotherapy  erlotinib as 1st line therapy, patients with EGFR mutated tumors had a better 
survival independent of therapy.  (5)  There are at present no published patient data regarding 
EGFR mutations under the influence of cetuximab-based therapy. However, preclinical data 
suggest that in contrast to the TKIs, NSCLC cell lines harboring EGFR mutations do not exhibit 
hypersensitivity to cetuximab.  (6) 
 
The prognostic and predictive value of EGFR protein expression by immunohistochemistry (IHC) 
has been studied in a relatively large number of reports, with mixed results, perhaps accounted for 
by heterogeneity in the patient populations studied as well as variability in methodologies.  In a 
meta-analysis by Meert, et al., using an eight-study subset, expression by IHC was modestly 
associated with a poor prognosis, HR 1.13, 95% confidence intervals 1.00-1.28).  (7)  In BR.21, 
using the DAKO EGFR Pharm Dx kit which defines positivity as > 10% of tumor cells staining, 
57% of tumors tested were positive.  EGFR protein expression defined in this manner was not a 
strong prognostic factor.  (2-3)  However, there was predictive value.  In IHC-positive patients 
receiving erlotinib, the HR for survival was 0.68 (p=0.02), without a significant interaction 
coefficient (p=0.25).  (2)  The ISEL study of gefitinib versus placebo showed a HR=0.77 (0.56, 
1.08) with a borderline significant interaction coefficient (p=0.05).  (4)  In the BR.21 study there 
was no difference in survival between erlotinib versus placebo in IHC-negative patients, while in 
the ISEL study IHC-negative patients had a tendency to shorter survival with gefitinib (HR=1.57 
(0.86, 2.87).  No similar data regarding EGFR protein expression are yet available for cetuximab-
based therapy in NSCLC.  
 


 
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EGFR FISH appears to have both prognostic and predictive implications in NSCLC. The concept 
of EGFR FISH as a predictive biomarker for EGFR TKIs originated with SWOG investigators, and 
the Colorado group, who also developed the assay classification system that has been commonly 
used, as previously reported in SWOG efforts such as S0126 (a Phase II trial of gefitinib in 
advanced BAC).  (8-10)  EGFR FISH has previously demonstrated predictive value for efficacy of 
the EGFR TKIs gefitinib and erlotinib in advanced NSCLC in a number of clinical studies, including 
BR.21 and ISEL, in which the Colorado scoring criteria was used, either by the Colorado group 
themselves, or by other investigators. No such data regarding EGFR FISH as a predictive marker 
exist for the monoclonal antibody cetuximab plus chemotherapy until now, as described in our 
recent report discussed below.  (11) 
 
Limited studies performed to date suggest that EGFR FISH is associated with a poor prognosis in 
NSCLC. Hirsch et al. first studied the prognostic association of EGFR gene copy number in 
surgically resected NSCLC.  In this study, increased gene copy number was associated with 
reduced survival (p=0.13). When combined with EGFR protein expression, the combination group 
with high EGFR FISH and high protein expression score (> 300 by H-score [= intensity x % 
positive cells]) had the worst survival (p=0.01).  (9)  The prognostic associations of EGFR FISH 
can also be derived from the two large randomized placebo-controlled studies, BR.21 and ISEL. In 
the ISEL study with gefitinib versus placebo, the median survival in the placebo arm was 4.5 
months in the FISH-positive group versus 6.2 months in the FISH-negative group (interaction test, 
p=0.004).  (4)  In the BR.21 study of erlotinib versus placebo the median survival in the placebo 
arm was estimated to be 4.5 months for the EGFR FISH-positive group versus 5.5 months for the 
FISH-negative group (interaction test, p=0.10).  (2)  A recent update of the BR.21 study by Zhu, et 
al., shows that only EGFR FISH-positive status was prognostic for worse survival (p=0.025) and 
predictive of differential survival benefit from erlotinib (p=0.005).  (3)  Thus, both ISEL and BR.21 
point to EGFR FISH-positivity as a poor prognostic factor, in the absence of EGFR TKI therapy.  
Others have also reported a poor prognosis in EGFR FISH-positive patients with NSCLC, 
particularly in squamous cell histology.  (12)  An association of EGFR FISH with poor prognosis 
has been reported in head and neck cancer as well.  (13)  In NSCLC patients treated with 
chemotherapy alone, (pertinent to interpretation of the S0342 data) there were no differences in 
outcomes between EGFR FISH-positive and FISH-negative groups for PFS (p=0.39) or OS 
(p=0.82).  (14) Taken together, these data suggest that EGFR FISH positivity portends a relatively 
poor prognosis in NSCLC (we believe an analogy may be drawn to HER2 FISH positivity in breast 
cancer). 
 
S0342 was a recently completed Phase II selection design study of chemotherapy (paclitaxel-
carboplatin) with either sequential or concurrent cetuximab (see figures below), conducted to 
determine whether one schedule or the other was preferable for subsequent Phase III testing 
against chemotherapy alone (current S0819 proposal).  Two hundred twenty-nine patients with 
advanced NSCLC were enrolled in the study.  EGFR FISH was performed in 76 patients with 
available tumor tissue, and classified as positive according to the Colorado scoring criteria.  (11)  
This FISH patient cohort had no significant differences in clinical characteristics or outcomes when 
compared with the overall study group.  As described here, SWOG translational medicine 
investigators observed a striking and unprecedented finding that increased EGFR gene copy 
number by FISH was associated with clinical benefit from cetuximab plus chemotherapy.  (11)  
Objective response (CR/PR) was numerically higher in FISH-positive patients (45%) versus FISH-
negative patients (26%, p=0.14), while disease control rate (CR/PR plus stable disease) was 
statistically superior (81% versus 55%, p=0.02).  Patients with FISH-positive tumors had a median 
progression-free survival of 6 months versus 3 months for FISH-negative patients (p=0.0008). 
Median survival was 15 months for FISH-positive patients versus 7 months for those who were 
FISH-negative (p=0.04).  Furthermore, survival favored FISH-positive patients receiving 
concurrent therapy, and was statistically positive only in the concurrent arm. These results are the 
first to suggest that EGFR FISH is a predictive factor for selection of NSCLC patients for 
cetuximab plus chemotherapy.  We believe these preliminary data are encouraging for all efficacy 
parameters and warrant further prospective testing. 
 


 
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Figure 1: S0342 Phase II Selection Design Schema 
 
 
 
Figure 2: S0342 Analysis by EGFR FISH 
 
 
 
 
  
 
 


 
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As can also be discerned from these recently published data and as noted in our paper, the 
improved outcomes with EGFR FISH positivity in S0342 appear even more interesting when the 
underlying poor prognosis of this group is taken into account.  (11)  We hypothesize that this 
observation does represent a treatment effect, perhaps similar to that of trastuzumab improving 
survival of HER2 FISH-positive breast cancer patients, a poor prognosis subgroup.  However, we 
acknowledge that due to the relatively small sample size and retrospective nature of the data, that 
our observations in S0342 are only hypothesis-generating. Nevertheless, these concepts are 
addressable in S0819. 
 
Even more recently, SWOG completed a Phase II trial (S0536) in 99 patients testing the 
combination of carboplatin, paclitaxel, bevacizumab and cetuximab.  This study, for which the 
primary endpoint was incidence of hemorrhagic toxicity, has shown this 4-drug regimen to be safe 
for future study with an acceptable toxicity profile when compared with either our S0342 results or 
the E4599 results.  Specifically, the incidence of toxicity ≥ Grade 4 was 31.5% in S0342 versus 
29.4% in S0536.  The rate of Grade 4 or worse hemorrhagic toxicity was 2%.  Fatal toxicities 
occurred in 3/85 (3.5%) patients on S0536, exactly the same rate as in E4599. Thus, the toxicity 
profile of the S0536 regimen (paclitaxel/carboplatin/bevacizumab/cetuximab) appears acceptable 
when compared with either E4599 (paclitaxel/carboplatin/bevacizumab) or a paclitaxel/ 
carboplatin/cetuximab regimen. 
 
Secondary endpoints of S0536 included PFS and OS.  Realizing that S0536 is a single arm Phase 
II trial, PFS of 7 months and OS of 14 months surpass the efficacy of any prior SWOG trial, by 2-3 
months for each endpoint.. Most importantly, there is no hint of a negative efficacy signal, the 
concern raised by the panitumumab trial in colorectal cancer. Therefore, we conclude that S0536 
has demonstrated both safety (the primary objective) and promising efficacy. 
 
KRAS mutation  
KRAS mutations, typically associated with tobacco-induced carcinogenesis in NSCLC, have been 
correlated with a poor prognosis, independent of therapeutic intervention.  However, in surgically 
resected early stage NSCLC, a recent report from the BR.10 trial showed no significant prognostic 
association.  (23)  Studies with EGFR TKIs in NSCLC have also shown that patients with KRAS 
mutations respond poorly to EGFR TKIs. The update from the BR.21 study shows a significant 
survival benefit with erlotinib in patients with wt KRAS (median survival 7.5 months (HR=0.69, 
p=0.03).  Patients with KRAS-mutated tumors had a median survival of 3.7 months (HR=1.69, 
p=0.3).  (3)  In the recently presented INTEREST study (gefitinib versus docetaxel) there was no 
statistically significant association between KRAS mutation and outcome.  (15) 
 
KRAS mutations in colon cancer have recently been reported to be a negative selection factor for 
patients receiving cetuximab-based therapy. In the Crystal study presented at ASCO 2008, adding 
cetuximab to FOLFIRI in metastatic colorectal cancer led to a significant increase in PFS (HR=.85, 
p=0.048).  However, the benefit of cetuximab plus FOLFIRI was much greater in patients with 
KRAS wild-type tumors (HR=0.68, p=0.017).  (16)  In Cairo2, a randomized trial of capecitabine, 
oxaliplatin and bevacizumab with and without cetuximab, although response rates, disease control 
rates and OS were identical between the two study arms, PFS was 10.7 months in the control arm 
versus 9.6 months with cetuximab, p=0.018.  (24)  PFS in the two study arms was similar in KRAS 
wt tumor patients, but decreased with cetuximab in KRAS mutant tumor patients, 12.5 versus 8.6 
months, p=0.043. OS in patients with KRAS mutant tumors was 18.1 months with cetuximab 
versus 24.9 months without, p=0.35.  These data suggest a significant impact of KRAS mutation 
on cetuximab efficacy in colorectal cancer. 
 
We submit that colorectal cancer and NSCLC are fundamentally different in several aspects 
pertinent to this issue, including molecular epidemiology of KRAS mutation (smoking-related in 
NSCLC), heterogeneity of histology in NSCLC (incidence of KRAS mutation 40-50% in colorectal 
cancer versus 20% overall in NSCLC, about 30% in adenocarcinomas), underlying EGFR-related 
biology (lack of EGFR mutations in colon cancer), and comparative activity of EGFR-directed  


 
S0819 
 
Page 12 
 
Version Date 10/3/16 
 
 
 
 
therapies (low activity of EGFR TKIs in colon cancer).  Thus, the implications of the recent colon 
data in regard to the current proposal are uncertain.  There are currently no published data 
correlating KRAS mutation and patient outcomes with cetuximab-based therapies in NSCLC, 
although we do now have limited data from S0342, as detailed below. 
 
In S0342, a smaller number of analyzable tumor specimens remained for KRAS testing after initial 
EGFR pathway testing, limiting interpretation of the analysis.  Determination of KRAS mutation in 
tumor DNA shed into plasma by scorpion-ARMS technology was performed to supplement the 
tissue analysis.  Shown below are results in tissue alone versus tissue plus plasma. In these 
limited data sets, response rates and disease control rates appear similar between patients with 
wild type and mutant KRAS tumor, as does PFS (median 4 months in both wild type and mutant 
KRAS patients). 
 
S0342 KRAS Analysis for Response: Tissue alone 
 
Wild type 
N=28 
Mutant  
N=17 
p-value 
Response 
5 (18%) 
5 (29 %) 
0.47 
Disease control 
17 (61%) 
12 (71%) 
0.54 
 
S0342 Analysis for Response: Tissue + Plasma 
 
Wild type 
N=83 
Mutant 
N=27 
p-value 
Response 
22 (27%) 
9 (33 %) 
0.62 
Disease control 
61 (73%) 
19 (70%) 
0.81 
 
 
 
 
 
S0342 Analysis for PFS: Tissue Alone   S0342 Analysis for PFS: Tissue + Plasma 
 
 
 
 
 
 
 
 
 
 
As shown below, while OS is somewhat higher in KRAS wild type tumor patients in the 
S0342 analysis, in the absence of a higher response rate or PFS, this difference in OS may 
reflect only the prognostic effects of KRAS. 
 
S0342 Analysis for OS: Tissue Alone  
S0342 Analysis for OS: Tissue + Plasma 
 
 
 
 
 
 
Progression-free survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
27
83
Events
26
81
Median
in Months
4
4
P = .65
Mutant
Wild-type
Progression-free survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
17
28
Events
16
26
Median
in Months
4
4
P = .38
Mutant
Wild-type
Progression-free survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
27
83
Events
26
81
Median
in Months
4
4
P = .65
Mutant
Wild-type
Progression-free survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
27
83
Events
26
81
Median
in Months
4
4
P = .65
Mutant
Wild-type
Progression-free survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
17
28
Events
16
26
Median
in Months
4
4
P = .38
Mutant
Wild-type
Progression-free survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Mutant
Other
N
17
28
Events
16
26
Median
in Months
4
4
P = .38
Mutant
Wild-type
Overall  survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Other
Mutant
N
28
17
Events
24
13
Median
in Months
13
7
P = .53
Wild-type
Mutant
Overall  survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
48
Months After Registration
Other
Mutant
N
83
27
Events
69
23
Median
in Months
11
8
P = .39
Wild-type
Mutant
Overall  survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Other
Mutant
N
28
17
Events
24
13
Median
in Months
13
7
P = .53
Wild-type
Mutant
Overall  survival
by KRAS in tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
Months After Registration
Other
Mutant
N
28
17
Events
24
13
Median
in Months
13
7
P = .53
Wild-type
Mutant
Overall  survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
48
Months After Registration
Other
Mutant
N
83
27
Events
69
23
Median
in Months
11
8
P = .39
Wild-type
Mutant
Overall  survival
by KRAS in plasma or tissue
0%
20%
40%
60%
80%
100%
0
12
24
36
48
Months After Registration
Other
Mutant
N
83
27
Events
69
23
Median
in Months
11
8
P = .39
Wild-type
Mutant


 
S0819 
 
Page 13 
 
Version Date 10/3/16 
 
 
 
 
It is our understanding that KRAS analysis from FLEX and BMS 099 have recently been 
completed, and that the results mimic those described above for S0342.  In summary, the limited 
KRAS data in NSCLC patients treated with cetuximab do not present a compelling argument to 
exclude KRAS mutant tumor patients from the proposed S0819 trial. While the major correlative 
science goal of the proposed S0819 trial is to define the role of EGFR FISH in optimizing 
outcomes from cetuximab-based chemotherapy, this Phase III study will also provide a unique 
patient and specimen resource for prospective testing of KRAS mutations.  As discussed below, 
the statistical design has been altered to accommodate real time testing for KRAS mutations, so 
that results can be considered at time of interim analysis. 
 
Significance 
 
The importance of the S0819 proposal is emphasized by the results of four previously published 
Phase III trials of chemotherapy with or without the EGFR TKIs gefitinib and erlotinib (INTACT I 
and II, TRIBUTE, TALENT) and two recent Phase III trials testing chemotherapy with or without 
cetuximab in advanced stage NSCLC. None of the four EGFR TKI trials showed benefit for the 
combination in any outcome parameter: response, PFS, or OS. Instead, for some parameters, 
numerically higher results were observed in placebo arms.  For example, in INTACT I, median OS 
was 9.9 months in each gefitinib arm versus 10.9 months in the placebo arm.  In an analysis by 
Hirsch, et al., of limited tumor specimens available from TRIBUTE, patients who were EGFR FISH-
positive seemed to do particularly poorly with chemotherapy plus erlotinib, when compared to 
chemotherapy plus placebo (response rate 29.8% in the placebo arm, 11.6% in the erlotinib arm).  
(25)  These data may conceivably reflect a negative interaction between concurrent chemotherapy 
and EGFR TKIs, as hypothesized by Gandara, et al.  (17)  Results of the two cetuximab-
chemotherapy trials appear more favorable.  The first, BMS 099, a trial of 676 patients, 
demonstrated no statistical improvement in the primary endpoint of radiology review-determined 
PFS between carboplatin-paclitaxel with or without cetuximab in unselected NSCLC patients (4.4 
versus 4.2 months, HR=0.9, 95% CI 0.76-1.06, p=0.23).  (18)  Investigator-determined PFS was 
more positive. BMS 099 was designed with a 90% power at the 5% level to reject the null 
hypothesis of no PFS difference between treatment arms, given a true hazard ratio of 0.75. 
Response rate was higher in the cetuximab arm: 25.7% versus 17.2%, p=0.0066. Survival data in 
BMS 099 have been recently presented.  The modest overall survival differences, 9.7 months for 
chemotherapy-cetuximab and 8.4 months for chemotherapy alone, are similar in magnitude to the 
FLEX data, and were not significantly different. 
 
In the preliminary report of the FLEX trial at ASCO 2008, a larger randomized study of 1,400 
patients comparing cisplatin-vinorelbine with or without cetuximab as first line therapy, the primary 
endpoint of a 25% improvement in survival was not achieved.  However, given the large sample 
size the trial did demonstrate a statistically significant survival advantage (HR=.87, p=0.04) with 
the combination.  Subset analysis showed benefit across most major subgroups, with the 
exception of race, where Asians did not benefit from the combination. Response rate and time to 
progression were in favor of the combination, while there was no difference in PFS between the 
two study arms.  Thus, while FLEX can be considered a positive study, the results leave many 
questions open regarding the exact role of cetuximab-chemotherapy in NSCLC.  Of note, FLEX 
patients were selected based on EGFR protein expression (IHC), whereas there was no selection 
process in BMS 099.  (19) 
 
Taken together, we believe the clinical trials summarized above suggest fundamental differences 
in how chemotherapy interacts with EGFR TKIs versus the monoclonal antibody cetuximab in 
NSCLC, which can be further exploited by biomarker selection of patients most likely to benefit. 
EGFR FISH has considerable potential to change practice and impact patient care for patients 
receiving cetuximab plus chemotherapy.  While the FLEX study results can be considered a 
positive lead, selection was based on IHC positivity only (1 EGFR positive cell), an EGFR 
biomarker of questionable significance.  EGFR FISH offers a potentially better way to select 
patients for this combination therapy (given the data presented in the background), and is highly  


 
S0819 
 
Page 14 
 
Version Date 10/3/16 
 
 
 
 
applicable to clinical practice.  Routine use of FISH technology is widespread. HER 2 FISH is 
performed on paraffin embedded material routinely for selection of breast cancer patients for 
trastuzumab therapy, and adoption of EGFR FISH could similarly become practice changing.  The 
current proposed Phase III trial is statistically designed to address both the clinical role of 
cetuximab using an "all comer" design, and the biologic role of EGFR FISH in maximizing efficacy.  
Further data from S0536 provide the basis for inclusion of bevacizumab in "bevacizumab-
appropriate" patients.  Considering the current state of therapy for advanced NSCLC, it is likely 
that the results of S0819 will significantly alter clinical practice. 
 
Inclusion of Women and Minorities: 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex categories 
is shown in the table below, however all institutions will be encouraged to make every effort to 
increase accrual in minority populations. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
19 
22 
41 
Not Hispanic or Latino 
773 
732 
1505 
Ethnic Category: Total of all subjects 
792 
753 
1546 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
15 
19 
34 
Black or African American 
80 
83 
163 
Native Hawaiian or other Pacific Islander 
2 
2 
4 
White 
694 
649 
1343 
Racial Category: Total of all subjects 
792 
753 
1546 
  
3.0 
DRUG INFORMATION 
 
3.1 
Bevacizumab (rhuMAb VEGF) (Avastin) (NSC #704865)  
 
a. 
DESCRIPTION   
 
Bevacizumab is a recombinant humanized monoclonal antibody that inhibits 
vascular endothelial growth factor (VEGF) resulting in inhibition of angiogenesis.  
Of the identified angiogenic factors, vascular endothelial growth factor (VEGF; 
also known as vascular permeability factor) is the most potent and specific and 
has been identified as a crucial regulator of both normal and pathologic 
angiogenesis.  VEGF produces a number of biologic effects, including endothelial 
cell mitogenesis and migration, induction of proteinases leading to remodeling of 
the extracellular matrix, increased vascular permeability, maintenance of survival 
for newly formed blood vessels, and, possibly, suppression of dendritic cell 
antigen presentation.  The biologic effects of VEGF are mediated through binding 
and stimulation of two receptors on the surface of endothelial cells: Flt-1 (fms-like 
tyrosine kinase)/VEGFR-1 and KDR (kinase domain region)/VEGFR-2. 
 


 
S0819 
 
Page 15 
 
Version Date 10/3/16 
 
 
 
 
Increased levels of VEGF expression have been found in most human tumors 
examined to date, including tumors of the lung, breast, thyroid, gastrointestinal 
tract, kidney, bladder, ovary, and cervix, angiosarcomas, glioblastomas, as well as 
multiple myeloma, lymphoma, and AML.  Inhibition of VEGF using an anti-VEGF 
monoclonal antibody blocks the growth of a number of human cancer cell lines in 
nude mice.  The human cancers represented by these cell lines that are 
growth-inhibited by anti-VEGF antibody include non–small cell lung cancer 
(Calu-6), colorectal cancer (LS174T, HM-7, LSLiM6), breast cancer (MCF-7), 
prostate cancer (D-145), head and neck cancer (KB), ovarian cancer (SK-OV-3), 
and others. 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Bevacizumab (NSC #704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even
ts.htm for further clarification.  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 
 
Version 2.4, May 23, 20161 
 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540]
 
Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER)
Likely (>20%) 
Less Likely 
(<=20%)
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS
 
 
Anemia 
 
Anemia (Gr 3) 
 
 
Blood and 
lymphatic system 
disorders - Other 
(renal thrombotic 
microangiopathy) 
 
 
Febrile  
neutropenia
 
Febrile neutropenia 
(Gr 3) 


 
S0819 
 
Page 16 
 
Version Date 10/3/16 
 
 
 
 
CARDIAC DISORDERS
 
 
 
Acute coronary 
syndrome2 
 
 
Cardiac disorders -
Other 
(supraventricular 
arrhythmias)3 
 
Cardiac disorders - 
Other 
(supraventricular 
arrhythmias)3 (Gr 3) 
 
Heart failure
 
 
 
Left ventricular 
systolic 
dysfunction 
 
 
 
Myocardial 
infarction2 
 
 
 
Ventricular 
arrhythmia 
 
 
 
Ventricular 
fibrillation 
 
GASTROINTESTINAL DISORDERS
 
 
Abdominal pain 
 
Abdominal pain (Gr 
3) 
 
Colitis 
 
Colitis (Gr 3) 
 
Constipation
Constipation (Gr 3)
 
Diarrhea 
 
Diarrhea (Gr 3) 
 
Dyspepsia
Dyspepsia (Gr 2)
 
 
Gastrointestinal 
fistula4 
 
 
Gastrointestinal 
hemorrhage5 
 
Gastrointestinal 
hemorrhage5 (Gr 2)
 
Gastrointestinal 
obstruction6 
 
 
 
 
Gastrointestinal 
perforation7 
 
 
 
Gastrointestinal 
ulcer8 
 
 
Ileus 
 
 
 
Mucositis oral
Mucositis oral (Gr 3)
 
Nausea 
 
Nausea (Gr 3) 
 
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Fatigue
Fatigue (Gr 3)
 
Infusion related 
reaction
 
Infusion related 
reaction (Gr 2)
 
Non-cardiac chest 
pain
 
Non-cardiac chest 
pain (Gr 3)
 
Pain 
 
Pain (Gr 3) 
HEPATOBILIARY DISORDERS
 
 
 
Gallbladder 
perforation
 
IMMUNE SYSTEM DISORDERS
 
 
Allergic reaction 
 
Allergic reaction (Gr 
2) 
 
Anaphylaxis
 


 
S0819 
 
Page 17 
 
Version Date 10/3/16 
 
 
 
 
INFECTIONS AND INFESTATIONS
 
 
Infection9 
Infection9 (Gr 3)
 
 
Infections and 
infestations - Othe
(necrotizing 
fasciitis)
 
 
Infections and 
infestations - Other 
(peri-rectal abscess
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS  
 
 
Injury, poisoning 
and procedural 
complications - 
Other (anastomotic
leak)10 
 
 
Wound complication 
Wound complication 
(Gr 2) 
 
Wound dehiscence  
Wound dehiscence 
(Gr 2) 
INVESTIGATIONS
 
 
Alanine 
aminotransferase 
increased 
 
Alanine 
aminotransferase 
increased (Gr 3) 
 
Alkaline 
phosphatase 
increased
 
Alkaline phosphatase
increased (Gr 3) 
 
Aspartate 
aminotransferase 
increased 
 
Aspartate 
aminotransferase 
increased (Gr 3) 
 
Blood bilirubin 
increased 
 
Blood bilirubin 
increased (Gr 2) 
 Creatinine 
increased 
 
 
Neutrophil count decreased 
 
 
Neutrophil count 
decreased (Gr 3) 
 
Platelet count 
decreased 
 
Platelet count 
decreased (Gr 4) 
 
Weight loss
Weight loss (Gr 3)
 
White blood cell 
decreased
 
White blood cell 
decreased (Gr 3)
METABOLISM AND NUTRITION DISORDERS
 
 
Anorexia 
 
Anorexia (Gr 3) 
 
Dehydration
Dehydration (Gr 3)
 
Hyperglycemia 
 
 
 
Hypokalemia
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia
Arthralgia (Gr 3)
 
 
Avascular 
necrosis11 
 
 
Generalized 
muscle weakness
 
 


 
S0819 
 
Page 18 
 
Version Date 10/3/16 
 
 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS (contd.)
 
 
Musculoskeletal 
and connective 
tissue disorder - 
Other (bone 
metaphyseal 
dysplasia)12 
 
 
 
Myalgia 
 
Myalgia (Gr 3) 
 
Osteonecrosis of 
jaw13 
 
 
NERVOUS SYSTEM DISORDERS
 
 
Dizziness 
 
Dizziness (Gr 2) 
 
Headache
Headache (Gr 3)
 
 
Intracranial 
hemorrhage
 
 
 
Ischemia 
cerebrovascular2 
 
 
Peripheral sensory 
neuropathy14 
 
 
 
 
Reversible 
posterior 
leukoencephalop
athy syndrome 
 
 
Syncope 
 
 
RENAL AND URINARY DISORDERS
 
 
Acute kidney injury 
 
Hematuria 
 
Hematuria (Gr 3) 
 
Proteinuria
Proteinuria (Gr 2)
 
 
Renal and urinary 
disorders - Other 
(nephrotic 
syndrome)
 
 
 
Urinary fistula 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
 
Reproductive system and 
breast disorders - Other 
(ovarian failure)15 
 
 
 
 
Vaginal fistula 
 
 
Vaginal hemorrhage 
Vaginal hemorrhage 
(Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Allergic rhinitis 
 
Allergic rhinitis (Gr 
3) 
 
 
Bronchopleural 
fistula 
 
 
 
Bronchopulmonar
y hemorrhage 
 
 
Cough
Cough (Gr 3)
 
Dyspnea 
 
Dyspnea (Gr 2) 
 
Epistaxis
Epistaxis (Gr 3)


 
S0819 
 
Page 19 
 
Version Date 10/3/16 
 
 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS (contd.)
 
 
Hoarseness 
 
Hoarseness (Gr 3) 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(nasal-septal 
perforation) 
 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders - Other 
(tracheo-
esophageal 
fistula)
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
 
 
Dry skin
 
 
Erythroderma 
 
 
 
 
Palmar-plantar 
erythrodysesthe
sia syndrome 
 
 
Pruritus
Pruritus (Gr 2)
 
Rash maculo-
papular
 
Rash maculo-
papular (Gr 2)
 
Urticaria 
 
Urticaria (Gr 2) 
VASCULAR DISORDERS
 
Hypertension 
 
 
Hypertension (Gr 3) 
 
Thromboembolic 
event 
 
Thromboembolic 
event (Gr 3) 
 
 
Vascular 
disorders - Other 
(arterial 
thromboembolic 
event)2,16 
 
 
1 
This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2 
The risks of arterial thrombosis such as cardiac or CNS ischemia are increased 
in elderly patients and in patients with a history of diabetes. 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial 
fibrillation, and atrial flutter. 
4 
Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal 
fistula, Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Rectal fistula, 
and other sites under the GASTROINTESTINAL DISORDERS SOC. 
5 
Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, 
Oral 
hemorrhage, 
Rectal 
hemorrhage, 
and 
other 
sites 
under 
the 
GASTROINTESTINAL DISORDERS SOC. 
6 
Gastrointestinal obstruction may include: Colonic obstruction, Duodenal 
obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, 
Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 


 
S0819 
 
Page 20 
 
Version Date 10/3/16 
 
 
 
 
7 
Gastrointestinal perforation may include: Colonic perforation, Duodenal 
perforation, Esophageal perforation, Gastric perforation, Jejunal perforation, 
Rectal perforation, and Small intestinal perforation. 
8 
Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric 
ulcer, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
9 
Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
10 Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal 
anastomotic leak; Large intestinal anastomotic leak; Rectal anastomotic leak; 
Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic leak. 
11 There have been reports of non-mandibular osteonecrosis (avascular necrosis) 
in patients under the age of 18 treated with bevacizumab. 
12 Metaphyseal dysplasia was observed in young patients who still have active 
epiphyseal growth plates. 
13 Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients 
in association with bevacizumab treatment, the majority of whom had received 
prior or concomitant treatment with i.v. bisphosphonates. 
14 Increased rate of peripheral sensory neuropathy has been observed in trials 
combining bevacizumab and chemotherapy compared to chemotherapy alone.  
15 Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-
stimulating hormone (FSH) elevation (≥30 mIU/mL), was increased in patients 
receiving adjuvant bevacizumab plus mFOLFOX compared to mFOLFOX 
alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of 
menses and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of 
these women.  Long term effects of bevacizumab exposure on fertility are 
unknown. 
16 Arterial thromboembolic event includes visceral arterial ischemia, peripheral 
arterial ischemia, heart attack, and stroke. 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable 
possibility that bevacizumab (rhuMAb VEGF) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (idiopathic thrombocytopenia purpura); Bone marrow 
hypocellular; Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block 
first degree; Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive 
cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other 
(tympanic membrane perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; 
Eye disorders - Other (blindness); Eye disorders - Other (conjunctival 
hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye disorders - 
Other (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm 
Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; Keratitis; Optic nerve 
disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry 
mouth; Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; 
Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral pain; Pancreatitis; 
Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 


 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death 
NOS; Edema face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like 
symptoms; Gait disturbance; Injection site reaction; Localized edema; Multi-organ 
failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder 
obstruction; Hepatic failure; Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; 
Bruising; Burn; Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood 
antidiuretic hormone abnormal; CD4 lymphocytes decreased; CPK increased; 
Carbon monoxide diffusing capacity decreased; Electrocardiogram QT corrected 
interval prolonged; Forced expiratory volume decreased; GGT increased; INR 
increased; Lipase increased; Lymphocyte count decreased; Serum amylase 
increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypomagnesemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; 
Back pain; Bone pain; Chest wall pain; Fibrosis deep connective tissue; Head soft 
tissue necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness 
upper limb; Musculoskeletal and connective tissue disorder - Other (aseptic 
necrotic bone); Musculoskeletal and connective tissue disorder - Other 
(myasthenia gravis); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue necrosis; 
Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous 
system necrosis; Cerebrospinal fluid leakage; Cognitive disturbance; Depressed 
level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; 
Extrapyramidal 
disorder; 
Facial 
nerve 
disorder; 
Hydrocephalus; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other 
(increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; 
Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; 
Insomnia; Libido decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; 
Cystitis noninfective; Renal and urinary disorders - Other (dysuria); Renal and 
urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; 
Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile 
dysfunction; Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary 
fibrosis; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal 
disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; 
Nail loss; Pain of skin; Photosensitivity; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and 
subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin 
hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; 
Phlebitis; Vasculitis  


 
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Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously associated 
with either agent. 
 
Based on clinical trials with bevacizumab as monotherapy or in combination with 
chemotherapy, the most common adverse events of any severity include asthenia, 
pain, headache, hypertension, diarrhea, stomatitis, constipation, epistaxis, 
dyspnea, dermatitis and proteinuria.  The most common Grade 3-4 adverse 
events were asthenia, pain, hypertension, diarrhea and leukopenia.  The most 
serious AEs include life-threatening or fatal hemorrhage, arterial thromboembolic 
events, gastrointestinal perforation and wound dehiscence; these events were 
uncommon but occurred at an increased frequency compared to placebo or 
chemotherapy controls in randomized studies.    
 
The following is a description of major adverse events associated with 
bevacizumab therapy.  Reference may also be made to the Investigator’s Brochure 
for bevacizumab.  The Package Insert (or Full Prescribing Information) was prepared 
for commercial Avastin but not the investigational bevacizumab being used in this 
protocol.  The Package Insert should therefore only be used in combination with the 
Investigator’s Brochure. 
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar 
leukoencephalopathy syndrome:  RPLS or clinical syndromes related to vasogenic 
edema of the white matter have been rarely reported in association with 
bevacizumab therapy (< 1%).  Clinical presentations are variable and may include 
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common risk factor and was present in most (though not all) patients on 
bevacizumab who developed RPLS.  MRI scans are key to diagnosis and typically 
demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images and 
hypointensity in T1 images) predominantly in the white matter of the posterior 
parietal and occipital lobes; less frequently, the anterior distributions and the gray 
matter may also be involved.  RPLS should be in the differential diagnosis in 
patients presenting with unexplained mental status change, visual disturbance, 
seizure or other CNS findings.  RPLS is potentially reversible, but timely correction 
of the underlying causes, including control of BP and interruption of the offending 
drug, is important in order to prevent progression to irreversible tissue damage. 
 
Infusion-Related Reactions:  Infusion reactions with bevacizumab were 
uncommon (< 3%) and rarely severe (0.2%).  Infusion reactions may include rash, 
urticaria, fever, rigors, hypertension, hypotension, wheezing, or hypoxia.  
Currently, there is no adequate information on the safety of retreatment with 
bevacizumab in patients who have experienced severe infusion-related reactions.  
 
Hypertension: Hypertension is common in patients treated with bevacizumab, with 
an incidence of 20-30% across trials.  Initiation or increase of anti-hypertensive 
medications may be required, but in most cases, blood pressure (BP) can be 
controlled with routine oral drugs.  However, incidents of hypertensive crisis with 
encephalopathy or cardiovascular sequelae have been rarely reported.  BP should 
be closely monitored during bevacizumab therapy and the goal of BP control 
should be consistent with general medical practice.  Bevacizumab therapy should 
be suspended in the event of uncontrolled hypertension. 
 
Proteinuria: Proteinuria has been seen in all bevacizumab studies to date, ranging 
in severity from an asymptomatic increase in urine protein (incidence of about 
20%) to rare instances of nephrotic syndrome (0.5% incidence).  Pathologic 
findings on renal biopsies in two patients showed proliferative glomerulonephritis.  
NCI-CTCAE Grade 3 proteinuria (> 3.5 gm/24 hour urine) is uncommon, but the 
risk may be higher in patients with advanced RCC.  In the Phase II randomized 
study in RCC, 24-hour urine was collected in a subset of patients enrolled, and 
Grade 3 proteinuria was found in 4 patients in the 10 mg/kg-arm (n=37), 2 patients 
in the 3mg/kg arm (n=35) and none in the placebo arm (n=38).  The safety of 
continuing bevacizumab in patients with moderate or severe proteinuria has not 
been adequately tested.   
 
Hemorrhage: The incidence of hemorrhage is increased with bevacizumab 
therapy.  Epistaxis is common, occurring in 20-40% of patients, but it is generally 
mild and rarely requires medical intervention.  Life-threatening and fatal 
hemorrhagic events have been observed in bevacizumab studies and included 
pulmonary hemorrhage, CNS bleeding and gastrointestinal (GI) bleeding.  In a 
Phase II study in non-small cell lung cancer, 6 cases of life-threatening 
hemoptysis or hematemesis were reported among 66 patients treated with 
bevacizumab and chemotherapy; 4 of these events were fatal (Novotny et al., 
2001).  In the pivotal Phase III trial in advanced colorectal cancer, the rate of GI 
hemorrhage (all grades) was 24% in the IFL/bevacizumab arm compared to 6% in 
the IFL arm; Grade 3-4 hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for 
IFL.  Serious GI hemorrhage has also been observed in clinical trials with 
bevacizumab in patients with pancreatic cancer or varices treated with 
bevacizumab.  
 


 
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Arterial Thromboembolic Events:  The risk of arterial thromboembolic events is 
increased with bevacizumab therapy, and such events included cerebral 
infarction, transient ischemic attack (TIA), myocardial infarction and other 
peripheral or visceral arterial thrombosis.  In the pivotal trial in CRC (AVF2107), 
the incidence of arterial thromboembolic events was 1% in the IFL/placebo arm 
compared to 3% in the IFL/ bevacizumab arm.  A pooled analysis of five 
randomized studies showed a two-fold increase in these events (4.4% vs. 1.9%).  
Certain baseline characteristics, such as age and prior arterial ischemic events, 
appear to confer additional risk (Schilling et al., ASCO 2005).  In patients ≥ 65 
years treated with bevacizumab and chemotherapy, the rate of arterial 
thromboembolic events was approximately 8.5%.  
 
Gastrointestinal Perforation/Fistula:  GI perforations/fistula were rare but occurred 
at an increased rate in bevacizumab-containing therapies.  The majority of such 
events required surgical intervention and some were associated with a fatal 
outcome.  In the pivotal Phase III trial in CRC (AVF2107), the incidence of bowel 
perforation was 2% in patients receiving IFL/bevacizumab and 4% in patients 
receiving 5-FU/bevacizumab compared to 0.3% in patients receiving IFL alone.  
GI perforation has also been reported in patients with gastric/esophageal cancer, 
pancreatic cancer, ovarian cancer or comorbid GI conditions such as diverticulitis 
and gastric ulcer.  GI perforation should be included in the differential diagnosis of 
patients 
on 
bevacizumab 
therapy 
presenting 
with 
abdominal 
pain 
or 
rectal/abdominal abscess. 
 
Wound Healing Complications:  Bevacizumab delays wound healing in rabbits, 
and it may also compromise or delay wound healing in patients. Bowel 
anastomotic dehiscence and skin wound dehiscence have been reported in 
clinical trials with bevacizumab.  The appropriate interval between surgery and 
initiation of bevacizumab required to avoid the risk of impaired wound healing has 
not been determined.  However, all clinical trials with bevacizumab have required 
a minimum of 28 days from prior major surgery; experience in the pivotal trial in 
advanced CRC suggests that initiation of bevacizumab 29-50 days following 
surgery should be associated with a very low incidence of wound dehiscence.  
The optimal interval between termination of bevacizumab and subsequent elective 
surgery has not been determined either.  In the pivotal study in CRC, 40 patients 
on the IFL/bevacizumab arm and 25 patients on the ILF/placebo arm underwent 
major surgery while on study; among them, significant post-operative bleeding or 
wound healing complications occurred in 4 of the 40 patients from the 
IFL/bevacizumab arm and none of the 25 patients from the IFL alone arm.  
Decisions on the timing of elective surgery should take into consideration the half-
life of bevacizumab (average 21 days, with a range of 11-50 days). 
 
Congestive Heart Failure:  The risk of left ventricular dysfunction may be 
increased in patients with prior or concurrent anthracycline treatment.  In a Phase 
III controlled clinical trial in metastatic breast cancer (AVF 2119g) in which all 
patients had received prior anthracyclines, congestive heart failure (CHF) or 
cardiomyopathy were reported in 7 patients (3%) in the bevacizumab/capecitabine 
arm compared to 2 (1%) in the capecitabine-only arm.  No increase in CHF was 
observed in CRC trials with bevacizumab in combination with IFL or 5-FU.   
 
Venous Thrombosis:  Venous thromboembolic events reported in bevacizumab 
trials included lower extremity deep vein thrombosis (DVT), pulmonary embolism 
and rarely, mesenteric or portal vein thrombosis.  In the pivotal Phase III trial of 
IFL ± bevacizumab (given at 5 mg/kg q2w), the overall incidences of Grade 3-4 
venous thromboembolic events were comparable in the two arms (15.1 vs. 
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Fertility and Pregnancy:  Clinical data are lacking regarding the immediate or long-
term effect of bevacizumab on fertility and pregnancy.  However, bevacizumab is 
known to be teratogenic and detrimental to fetal development in animal models.  
In addition, bevacizumab may alter corpus luteum development and endometrial 
proliferation, thereby having a negative effect on fertility.  As an IgG1, it may also 
be secreted in human milk.  Therefore, fertile men and women on bevacizumab 
studies must use adequate contraceptive measures and women should avoid 
breast feeding.  The duration of such precautions after discontinuation of 
bevacizumab should take into consideration the half-life of the agent (average 21 
days, with a range of 11 to 50 days). 
 
Immunogenicity:  As a therapeutic protein, there is a potential for immunogenicity 
with bevacizumab.  With the currently available assay with limited sensitivity, high 
titer human anti-bevacizumab antibodies have not been detected in approximately 
500 patients treated with bevacizumab.   
 
Neutropenia:  When combined with chemotherapy, bevacizumab increased the 
risk of neutropenia compared to chemotherapy alone.  In a Phase III trial with IFL 
± bevacizumab in colorectal cancer, Grade 3-4 neutropenia was 21% in the 
bevacizumab + IFL arm vs. 14% in the IFL arm (Grade 4 neutropenia was 3 vs. 
2%).  In the Phase III trial with carboplatin and paclitaxel ± bevacizumab in 
metastatic NSCLC, the bevacizumab-containing arm was associated with 
increased rates of Grade 4 neutropenia (26% vs. 17%), febrile neutropenia (5.4% 
vs. 1.8%) and an increased rate of infection with neutropenia (4.5 vs. 1.8%) with 3 
cases with fatal outcome in the bevacizumab + chemotherapy arm vs. 0 in the 
chemotherapy only control. 
 
Tracheoesophageal (TE) fistula:  In a Phase II trial of concurrent chemoradiation 
and 
bevacizumab 
in 
limited 
SCLC 
(concurrent 
irinotecan, 
carboplatin, 
radiotherapy, and bevacizumab, followed by maintenance bevacizumab), among 
the first 25 patients enrolled, there have been two confirmed cases of 
tracheoesophageal (TE) fistula (one fatal) and a third case of fatal upper 
aerodigestive tract hemorrhage, with TE fistula suspected but not confirmed.  All 
three events occurred during the bevacizumab maintenance phase (1.5 to 4 
months after completion of concurrent bevacizumab and chemoradiation).  The 
TE fistula rate in this trial was higher than expected with chemoradiation alone.  
While pulmonary fistula (including TE fistula) has also been observed in advanced 
NSCLC or SCLC patients receiving bevacizumab and chemotherapy (without 
radiation), the incidence was extremely low (<< 1%), and the relationships to 
treatment vs. tumor in those cases were unclear.  Experience is limited for 
bevacizumab administered sequentially after chemoradiation for either NSCLC or 
SCLC; in a study for chemoradiation followed by bevacizumab in SCLC, one of 
the 60 patients enrolled developed TE fistula. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  In study AVF0737g, the pharmacokinetics of bevacizumab appeared to 
be linear for doses of  1 mg/kg, with a half-life of ~15 days.  A consistent profile 
was seen in study AVF0761g.  Co-administration of bevacizumab with cytotoxic 
chemotherapy did not appear to result in a change in the systemic concentrations 
of the cytotoxic agents. 
 
How Supplied:  Bevacizumab is supplied as a clear to slightly opalescent, sterile 
liquid ready for parenteral administration.  For bevacizumab, each 400 mg (16 mL) 
and 100 mg (25 mg/mL – 4 mL fill) glass vial contains bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.   


 
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Preparation:  Vials contain no preservative and are intended for single use only.  
Place the calculated dose in 100 mL of 0.9% Sodium Chloride for Injection.  
Once the bevacizumab has been added to the bag with 0.9% Sodium Chloride for 
Injection, the solution must be administered within 8 hours.  When the 
bevacizumab IV bag is empty, an additional 50 ml of 0.9% Sodium Chloride for 
Injection should be added to the IV bag and the infusion continued for a volume 
equal to that of the tubing to insure complete delivery of the bevacizumab.  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 for Injection 
and infuse a volume equal to that of the tubing to insure complete delivery of the 
bevacizumab.  Note that this flush is not included in the infusion times. 
 
Storage and Stability:  Bevacizumab is only shipped Monday through Thursday.  It 
is shipped on blue ice for next day delivery.  On receipt, bevacizumab should be 
stored in the refrigerator (2o to 8oC) and should remain refrigerated until just prior 
to use.  Do not freeze.  Do not shake.  Shelf-life studies of bevacizumab are 
continuing.  Investigators will be notified of any dating extensions, when lots have 
expired, and how to handle disposition of the agent.  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 for Injection, 
solution of bevacizumab must be administered within 8 hours. 
 
Administration:  The route of administration is intravenous as a continuous 
infusion.  The initial dose should be administered over a minimum of 90 minutes.  
If no adverse reactions occur after the initial dose, 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. 
 
d. 
SUPPLIER   
 
Bevacizumab is commercially available and should be purchased by a third party.  
Bevacizumab will not be supplied by the NCI. 
 
Avastin Access Solutions provides coverage and reimbursement support, patient 
assistance and informational resources.  Please call 888/249-4918 (M - F 6:00 am 
- 5:00 pm PST) for assistance.  
  
Examples of how Avastin Access Solutions can help include the following: 
 
 
Conducting benefits investigations 
 
Obtaining prior authorizations for the use of Avastin when necessary 
 
Helping with appeals when prior authorization or reimbursement is denied 
 
Referring patients to independent, non-profit organizations for co-pay 
assistance 
 
Referring uninsured or rendered uninsured patients to the Genentech Access 
to Care 
 
Please refer to the Physician Desk Reference and package insert for 
complete information. 
 


 
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3.2 
Carboplatin (CBDCA) (NSC-241240) 
 
a. 
DESCRIPTION 
 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an 
analog of cisplatin, producing intrastrand DNA cross-links. 
 
b. 
TOXICOLOGY 
 
Human 
Toxicology: 
 
Side 
effects 
of 
carboplatin 
(CBDCA) 
include 
myelosuppression, nausea, vomiting, abdominal pain, diarrhea and constipation.  
Other toxicities include allergic reaction (including hypersensitivity, i.e., rash, 
urticaria, erythema, pruritus, bronchospasm and hypotension), peripheral 
neuropathy, paresthesia, loss of hair, hearing loss, visual disturbances and 
change in taste.  Serum creatinine elevations and blood urea elevations have 
occurred as well as abnormal liver function tests and decreased serum electrolyte 
values.  Although rare, pain, asthenia, cardiovascular, respiratory, genitourinary 
and mucosal side effects have occurred in some patients.  Cancer-associated 
hemolytic uremic syndrome has been reported rarely.  The renal effects of 
nephrotoxic compounds may be potentiated by carboplatin.  Carboplatin is 
contraindicated in patients with a history of severe allergic reactions to cisplatin or 
other platinum-containing compounds or mannitol.  This drug should not be used 
in patients with severe bone marrow depression or significant bleeding.  The 
occurrence of acute leukemia has been reported rarely in patients treated with 
anthracycline/alkylator combination chemotherapy.  
 
Pregnancy and Lactation:  Carboplatin may cause fetal harm, therefore women of 
childbearing potential should be advised to avoid becoming pregnant. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  The differences in potencies of carboplatin and cisplatin are due to 
differences in aquation rates.  The initial half-life is 1.1 - 2.0 hours and the post-
distributional half-life is 2.6 - 5.9 hours.  Sixty-five percent of the dose is excreted 
in the urine within twelve hours.  Carboplatin is not bound to plasma proteins. 
 
Formulation:  Carboplatin is supplied as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin for 
administration by intravenous injection.  Each vial contains equal parts by weight 
of carboplatin and mannitol.  Immediately before use, the content of each vial 
must be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in 
Water, or 0.9% Sodium Chloride Injection, USP, according to the following 
schedule: 
 
Vial Strength 
Diluent Volume 
 
 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL.  Carboplatin 
can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in 
Water or 0.9% Sodium Chloride Injection, USP (NS). 


 
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Storage and Stability:  Unopened vials of carboplatin for injection are stable for the 
life indicated on the package when stored at controlled room temperature 15° - 
30°C, and protected from light.  When reconstituted as directed, the solution of 
carboplatin exhibits no decomposition for 8 hours at room temperature (25°C).  
Like cisplatin, this drug should not be given through aluminum needles.  
CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be discarded 
eight hours after dilution. 
 
Administration:  Intravenous. 
 
Supplier:  Carboplatin is commercially available for purchase by the third party.  
This drug will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
REFERENCE - PDR 1993 
 
3.3 
Cetuximab (IMC-C225) (Erbitux®) (NSC-714692)  
 
a. 
DESCRIPTION  
 
Cetuximab, a chimerized antibody of the IgG1 subclass, was originally derived 
from a mouse myeloma cell line.  Cetuximab was genetically engineered by 
cloning the heavy and light chains of cetuximab and adapting them for expression 
together with the constant regions of the human kappa light chain and human 
gamma 1 heavy chain.  The chimerization resulted in an antibody with binding 
affinity to epidermal growth factor receptors (EGFR) greater than the natural 
ligand epidermal growth factor (EGF).  Cetuximab blocks binding of EGF and 
transforming growth factor alpha (TGF) to EGFR and inhibits ligand-induced 
activation of this tyrosine kinase receptor.  Cetuximab also stimulates EGFR 
internalization, effectively removing the receptor from the cell surface for 
interaction with ligand. 
 
b. 
TOXICOLOGY 
 
Pre-clinical toxicology of this drug was performed. A dose-response was 
demonstrated in sera after a single 15 minute intravenous infusion of cetuximab. 
Pharmacokinetic studies revealed a dose-response in sera after twice weekly 
infusions up to 28 days.  No evidence of accumulation of antibody was observed. 
Acute and subacute toxicity studies of single and repeated doses revealed no 
evidence of treatment-related effects in body weight, food consumption, clinical 
pathology or gross necropsy data were observed.  
 
A total of 606 subjects treated with cetuximab through February 2002 were tested 
for the presence of anti-cetuximab antibodies by analyzing pre- and post-
treatment sera using a double antigen radiometric assay. The incidence of an anti-
cetuximab immune response in these subjects was 4.1%.  When it occurred, the 
anti-cetuximab response was generally found to be weak (upper limit of normal is 
10 ng/ml cetuximab binding).  The anti-cetuximab antibodies from two subjects 
with the highest reactivity (4670 and 6516 ng/ml) did not interfere with the ability of 
cetuximab to inhibit proliferation in a cetuximab sensitive cell line, suggesting that 
the antibodies in these sera were non-neutralizing.  Levels of reactivity in sera 
from other subjects were not high enough to perform this type of  


 
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analysis. In order to determine the specificity of the antibody response, sera from 
15 subjects who had a positive anti-cetuximab response were further studied in 
the double antigen radiometric assay using unlabeled cetuximab as a competitor.  
This analysis demonstrated that sera from 14 of the 15 subjects contained 
cetuximab-specific antibodies. 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Cetuximab 
(NSC #714692) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This 
subset of AEs (ASAEL) contains events that are considered 'expected' for 
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm  for further clarification. Frequency is provided based on 2282 
patients. Below is the CAEPR for Cetuximab. 
 
 
Version 2.1, March 31, 20101 
 
 Adverse Events with Possible  
 Relationship to Cetuximab 
 (CTCAE 4.0 Term) 
[n= 2282] 
 
 
 
 EXPECTED 
AEs FOR 
CTEP-AERS 
REPORTING 
Agent Specific 
Adverse Event 
List 
(ASAEL)
Likely (>20%) 
Less Likely (<=20%) 
Rare but 
Serious (<3%) 
 
Expected 
BLOOD AND LYMPHATIC SYSTEM DISORDERS
  
 
 
  
EAR AND LABYRINTH DISORDERS
  
 
External ear 
inflammation
 
  
 
 
  
EYE DISORDERS
  
 
Conjunctivitis 
 
 Conjunctivitis 
 
Dry eye
 Dry eye
 
Uveitis 
 
 Uveitis 
 
Watering eyes
 Watering eyes
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal 
pain 
 
Cheilitis
 Cheilitis
 
Constipation 
 
 Constipation 
Diarrhea 
 Diarrhea
 
Dry mouth 
 
 Dry mouth 
 
Dyspepsia
 Dyspepsia
 
Mucositis oral 
 
 Mucositis oral 
 Nausea
 
Vomiting 
 
 Vomiting 


 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS   
 
Chills
 Chills
 
Edema limbs 
 
  
 Fatigue
 
 
 Fever 
 
Flu like symptoms 
 
 Flu like 
symptoms 
 
Infusion related reaction  
 Infusion related 
reaction 
 
Non-cardiac chest pain
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction
 
Anaphylaxis  
  
INFECTIONS AND INFESTATIONS
  
 
Infection2 
 
  
 
 Infections and 
infestations – 
Other (aseptic 
meningitis) 
  
INVESTIGATIONS
  
 
Neutrophil count 
decreased
 
  
 
Weight loss 
 
 Weight loss 
 
White blood cell decreased 
 White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS
  
 
Anorexia 
 
 Anorexia 
 
Dehydration
 Dehydration
 
Hypocalcemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnese
mia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia 
 
Back pain
 Back pain
 
Myalgia 
 
 Myalgia 
NERVOUS SYSTEM DISORDERS
  
Headache 
 
 
 Headache 
 
Syncope
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis
 Allergic rhinitis
 
Bronchospasm 
 
  
 
Cough
 Cough
 
Dyspnea 
 
 Dyspnea 
 
Hoarseness
 Hoarseness
 
Pneumonitis 
  
 
Respiratory, 
thoracic, and 
mediastinal 
disorders - Other 
(non-cardiogenic 
pulmonary 
edema)
  


 
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SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
a
 Alopecia
 
 
 Dry skin 
 
Nail loss
 Nail loss
 
 
Palmar-plantar 
erythrodysesthe
sia syndrome 
  
 
Photosensitivity
 Photosensitivity
 
Pruritus 
 
 Pruritus 
 
Purpura
  
Rash acneiform 
 
 
 Rash acneiform
Rash maculo-papular 
 
 
 Rash maculo-
papular 
 
Skin ulceration
  
 
Urticaria 
 
 Urticaria 
VASCULAR DISORDERS
  
 
Hypotension 
 
 Hypotension 
 
Thromboembolic event 
 
 Thromboem-
bolic event 
 
1 
This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The 
current 
version 
can 
be 
obtained 
by 
contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail. 
2 
Infection could include all 75 sites of infections under the INFECTIONS AND 
INFESTATIONS SOC. 
 
Also reported on cetuximab trials but with the relationship to cetuximab still 
undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated intravascular 
coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Left 
ventricular 
systolic 
dysfunction; 
Myocardial 
infarction; 
Paroxysmal 
atrial 
tachycardia; 
Pericardial 
effusion; 
Sinus 
bradycardia; 
Sinus 
tachycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eyelid function 
disorder; Keratitis; Photophobia; Vitreous hemorrhage 
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Esophagitis; Gastritis; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal hemorrhage 
(including Colonic or Gastric hemorrhage or hemorrhage in other sites under the 
GASTROINTESTINAL DISORDERS SOC); Gastrointestinal perforation (Colonic 
perforation, Duodenal perforation, or perforation in other sites under the 
GASTROINTESTINAL DISORDERS SOC); Gastrointestinal ulcer (ulcer includes 
Duodenal 
ulcer, 
Rectal 
ulcer, 
or 
ulcer 
in 
other 
sites 
under 
the 
GASTROINTESTINAL DISORDERS SOC); Ileus; Pancreatitis; Rectal fistula 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema 
face; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Wound dehiscence 


 
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INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; 
Creatinine increased; Platelet count decreased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperkalemia; Hyperuricemia; 
Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other 
(myasthenia); Musculoskeletal and connective tissue disorder - Other (Sudeck's 
Atrophy) 
NERVOUS 
SYSTEM 
DISORDERS 
- 
Ataxia; 
Dizziness; 
Dysgeusia; 
Extrapyramidal disorder; Intracranial hemorrhage; Nervous system disorders - 
Other (cholinergic syndrome); Neuralgia; Peripheral motor neuropathy; Peripheral 
sensory neuropathy; Seizure; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - 
Other (acute renal failure)  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system 
and breast disorders - Other (balanitis); Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Atelectasis; Bronchopulmonary hemorrhage; 
Epistaxis; Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other 
(bronchiolitis obliterans-organized pneumonia [BOOP]) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hirsutism; Skin 
hypopigmentation; Skin and subcutaneous tissue disorders - Other (skin fissures) 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Vasculitis 
 
Note: Cetuximab in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
Additional risks in older patients with NSCLC:  Based on a recent pooled 
analysis of randomized trials in patients with advanced NSCLC treated with 
platinum-based 
chemotherapy 
with 
or 
without 
cetuximab, 
cetuximab-
chemotherapy was associated with an increase in life-threatening events, some of 
which were fatal, in patients who were ≥ 65 years old, especially in those with a 
pre-existing cardiac history. 
 
Infusion Reactions:  In clinical trials, severe, potentially fatal infusion reactions 
were reported. These events include the rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. In studies in 
advanced colorectal cancer, severe infusion reactions were observed in 3% of 
patients receiving cetuximab plus irinotecan and 2% of patients receiving 
cetuximab monotherapy. Grade 1 and 2 infusion reactions, including chills, fever, 
and dyspnea usually occurring on the first day of initial dosing, were observed in 
16% of patients receiving cetuximab plus irinotecan and 23% of patients receiving 
cetuximab monotherapy.  
 
A 20-mg test dose was administered intravenously over 10 minutes prior to the 
loading dose to all patients in earlier studies.  The test dose did not reliably 
identify patients at risk for severe allergic reactions. 
 
Severe infusion reactions occurred with the administration of cetuximab in 
approximately 3% (17/633) of patients, rarely with fatal outcome (< 1 in 1,000). 
Approximately 90% of severe infusion reactions were associated with the first 
infusion of cetuximab despite the use of prophylactic antihistamines. These 
reactions were characterized by the rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. Caution must 
be exercised with every cetuximab infusion, as there were patients who 
experienced their first severe infusion reaction during later infusions.   


 
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Pulmonary Toxicity:  Interstitial lung disease (ILD) was reported in 3 of 633 (< 
0.5%) patients with advanced colorectal cancer receiving cetuximab. Interstitial 
pneumonitis with non-cardiogenic pulmonary edema resulting in death was 
reported in one case. Two patients had pre-existing fibrotic lung disease and 
experienced an acute exacerbation of their disease while receiving cetuximab in 
combination with irinotecan. In the clinical investigational program, an additional 
case of interstitial pneumonitis was reported in a patient with head and neck 
cancer treated with cetuximab and cisplatin. The onset of symptoms occurred 
between the fourth and eleventh doses of treatment in all reported cases. 
 
Dermatologic Toxicity:  In clinical studies of cetuximab, dermatologic toxicities, 
including acneiform rash, skin drying and fissuring, and inflammatory and 
infectious sequelae (e.g. blepharitis, cheilitis, cellulitis, cyst) were reported. In 
patients with advanced colorectal cancer, acneiform rash was reported in 88% 
(560/633) of all treated patients, and was severe (Grade 3 or 4) in 12% (79/633) of 
these patients. Subsequent to the development of severe dermatologic toxicities, 
complications including S. aureus sepsis and abscesses requiring incision and 
drainage were reported. 
 
Non-suppurative acneiform rash described as “acne”, “rash”, “maculopapular 
rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis” was observed in 
patients receiving cetuximab plus irinotecan or cetuximab monotherapy. One or 
more of the dermatological adverse events were reported in 88% (14% Grade 3) 
of patients receiving cetuximab plus irinotecan and in 90% (10% Grade 3) of 
patients receiving cetuximab monotherapy. Acneiform rash most commonly 
occurred on the face, upper chest, and back, but could extend to the extremities 
and was characterized by multiple follicular- or pustular-appearing lesions. Skin 
drying and fissuring were common in some instances, and were associated with 
inflammatory and infectious sequelae (e.g. blepharitis, cellulitis, cyst).  Two cases 
of S. aureus sepsis were reported.  The onset of acneiform rash was generally 
within the first two weeks of therapy. Although in a majority of the patients the 
event resolved following cessation of treatment, in nearly half of the cases, the 
event continued beyond 28 days. 
 
A related nail disorder, occurring in 14% of patients (0.3% Grade 3), was 
characterized as a paronychial inflammation with associated swelling of the lateral 
nail folds of the toes and fingers, with the great toes and thumbs as the most 
commonly affected digits. 
 
Hypomagnesemia 
 
The occurrence of hypomagnesemia has been reported. 
 
c. 
PHARMACOLOGY 
 
Pharmacokinetic modeling has been employed during cetuximab clinical studies 
with the objective of determining the dosing regimen(s) of cetuximab that 
maintains drug concentrations within a range associated with zero-order 
elimination (saturation of clearance).  The analyses suggest that complete 
saturation of the mechanism(s) governing drug elimination occur in the range of 
200 to 500 mg/m2, while doses of cetuximab below 200 mg/m2 are not associated 
with saturation of clearance.  Doses of  400 mg/m2 demonstrated zero-order 
elimination for at least 96 hours following drug infusion with increasing amounts of 
trough level drug accumulation.  Since this drug accumulation is an expected 
result 
when 
operating 
under 
saturating 
conditions, 
the 
model 
was  


 
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examined to identify cetuximab dose levels that maintained trough concentrations 
from initial dosing through all subsequent dosing at or just above Km. The dosing 
regimen ultimately selected to satisfy these requirements was one that utilized a 
loading dose of 400 mg/m2 followed by subsequent maintenance doses of 250 
mg/m2. 
 
Formulation:  Cetuximab is an anti-EGFR human-to-murine chimeric antibody. 
Cetuximab is expressed in SP2/0 myeloma cell line, grown in large scale cell 
culture bioreactors and purified to a high level purity using several purification 
steps including protein A chromatography, ion exchange chromatography, low pH 
treatment and nanofiltration. Cetuximab is not known to be a vesicant. 
 
How Supplied:  The product is formulated to 2 mg protein/mL with phosphate 
buffered saline, pH 7.2  0.2 and aseptically filled into sterile glass vials, 100 mg 
per 50 cc vial, and stored as a liquid at 2 to 8 °C.  Each vial contains the following 
active and inactive ingredients per 1.0 ml: 2 mg of cetuximab, 145 nmol/L sodium 
chloride, and 10 mmol/L sodium phosphate. 
  
Handling and Dispensing of Cetuximab:  Cetuximab should be stored in a secure 
area according to local regulations.  It is the responsibility of the investigator to 
ensure that cetuximab is only dispensed to study subjects.  The cetuximab must 
be dispensed only from official study sites by authorized personnel according to 
local regulations. 
 
Storage Requirement/Stability:  Store vials under refrigeration at 2C to 8C (36F 
to 46F). DO NOT FREEZE. Increased particulate formation may occur at 
temperatures at or below 0C. This product contains no preservatives. 
Preparations of cetuximab in infusion containers are chemically and physically 
stable for up to 12 hours at 2C to 8C (36F to 46F) and up to 8 hours at 
controlled room temperature (20C to 25C; 68F to 77F). Discard any remaining 
solution in the infusion container after 8 hours at controlled room temperature or 
after 12 hours at 2C to 8C.  Discard any unused portion of the vial. 
 
Preparation and Administration:  Cetuximab is supplied as a 50-mL, single-use 
vial containing 100 mg of cetuximab at a concentration of 2 mg/mL in phosphate 
buffered saline.  The solution should be clear and colorless and may contain a 
small amount of easily visible white amorphous cetuximab particulates.  DO NOT 
SHAKE OR DILUTE. 
 
Cetuximab must not be administered as an IV push or bolus.  
 
Cetuximab must be administered with the use of a low protein binding 0.22-
micrometer in-line filter.  
 
Cetuximab can be administered via infusion pump or syringe pump. 
 
Infusion Pump: 
 
 
Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike or other appropriate transfer device may be used). 
 
Fill cetuximab into a sterile evacuated container or bag such as glass 
containers, polyolefin bags (e.g. Baxter Intravia), ethylene vinyl acetate bags 
(e.g. Baxter Clintec), DEHP plasticized PVC bags (e.g. Abbott Lifecare), or 
PVC bags. 


 
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 
Repeat procedure until the calculated volume has been put in to the 
container.  Use a new needle for each vial. 
 
Administer through a low protein binding 0.22-micrometer in-line filter (placed 
as proximal to the patient as practical). 
 
Affix the infusion line and prime it with cetuximab before starting the infusion. 
 
Maximum infusion rate should not exceed 5 mL/min. 
 
Use 0.9% saline solution to flush line at the end of infusion. 
 
Syringe Pump: 
 
 
Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike may be used). 
 
Place the syringe into the syringe driver of a syringe pump and set the rate. 
 
Administer through a low protein binding 0.22-micrometer in-line filter rated for 
syringe pump use (placed as proximal to the patient as practical). 
 
Connect up the infusion line and start the infusion after priming the line with 
cetuximab. 
 
Repeat procedure until the calculated volume has been infused. 
 
Use a new needle and filter for each vial. 
 
Maximum infusion rate should not exceed 5 mL/min. 
 
Use 0.9% saline solution to flush line at the end of infusion. 
 
Cetuximab should be piggybacked to the patient’s infusion line. 
 
Following the cetuximab infusion, a 1-hour observation period is recommended. 
 
Safety Precautions:  Appropriate mask, protective clothing, eye protection, 
gloves, and Class II vertical-laminar-airflow safety cabinets are recommended 
during preparation and handling.  Opened vials must be disposed of at the 
investigational center as chemotherapy or biohazardous waste provided 
documented procedures for destruction are in place. For questions regarding 
cetuximab destruction please contact BMS at  
GMB-DC-ALL-ClinicalShipment@catalent.com.  
 
Cetuximab therapy should be used with caution in patients with known 
hypersensitivity to cetuximab, murine proteins, or any component of this product. 
It is recommended that patients wear sunscreen and hats and limit sun exposure 
while receiving cetuximab as sunlight can exacerbate any skin reactions that may 
occur. 
 
Administration of Cetuximab:  In an effort to prevent a hypersensitivity reaction, all 
patients should be premedicated with diphenhydramine hydrochloride 50 mg (or 
an equivalent antihistamine) by IV given 30 - 60 minutes prior to the first dose of 
cetuximab.  Premedication may be administered prior to subsequent doses, but at 
the investigator’s discretion, the dose of diphenhydramine (or similar agent) may 
be reduced. 
 
The initial dose of cetuximab is 400 mg/m2 intravenously administered over 120 
minutes, followed by weekly infusions at 250 mg/m2 IV over 60 minutes. The 
infusion rate of cetuximab must never exceed (5 mL/min). Patients must be 
continuously observed during the infusion for signs of anaphylaxis. 
 


 
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Patients will be closely monitored for treatment-related adverse events, especially 
hypersensitivity reactions, during the infusion and the post-infusion observation 
hour. For the duration that patients are on study therapy, adverse event 
monitoring will be done continuously. Patients will be evaluated for adverse events 
at each visit and are to be instructed to call their physician to report any clinically 
significant adverse events between visits. 
 
d. 
SUPPLIER 
 
Cetuximab is distributed free of charge through an alliance between ImClone 
Systems, Inc. and Bristol-Myers Squibb (BMS).  Quantities must be ordered in 
multiples of 20 (keeping in mind that 7 - 9 vials will be needed for an initial dose 
and 4 - 6 for a maintenance dose, depending on patient's BSA).  A suggested 
initial shipment is 20 vials.  Institutions should reorder when supply is low based 
on site needs. 
 
Following collection of all regulatory documents and patient registration, a supply 
of cetuximab may be ordered from BMS.  Investigators must email a completed 
Cetuximab Drug Request Form for S0819 to the BMS Clinical Supply Manager at 
GMB-DC-ALL-ClinicalShipment@catalent.com.  The form can be downloaded 
from the SWOG web site for utilization. 
 
Both initial and re-supply drug requests will require approximately 5 business 
days from receipt of the Cetuximab Drug Request Form to shipment of product.  
All product will be shipped via Federal Express in a temperature controlled 
container to ensure adequate refrigeration of the product.  To help segregate 
product for this study from other investigational or marketed product, stickers 
bearing the BMS protocol number will be provided and may be affixed to the outer 
carton so as not to obscure any marking.  The SWOG protocol number S0819 
may be added at the site to the same sticker if desired.  It is possible that sites 
may have more than one cetuximab clinical study ongoing at the same time.  It is 
imperative that only product designated for S0819 be utilized for this study.  
Cetuximab must be stored under refrigeration at +2° to +8° (+36° to +46°F).  DO 
NOT FREEZE CETUXIMAB.  Each shipment of cetuximab will contain an internal 
temperature gauge to ensure the product has remained at the appropriate 
temperature during shipping.  This information should be recorded on the 
appropriate drug accountability form.  For questions regarding cetuximab 
shipment please contact BMS at GMB-DC-ALL-ClinicalShipment@catalent.com. 
 
Destruction:  At the completion of each patient’s infusion, destroy any open vials 
according to institution guidelines.  At the completion of the study, all unused drug 
will be destroyed at the site, in accordance with all applicable regulations, 
guidelines and institution’s procedures.  Please maintain appropriate records of 
the disposal, including dates, quantities and method of destruction.   
 
3.4 
Paclitaxel, Taxol® (NSC-673089)  
 
a. 
DESCRIPTION 
 
Chemistry:  Paclitaxel is a diterpene plant product found in the needles and bark 
of the western yew, Taxus brevifolia.  The marketed formulation is prepared in a 
semi-synthetic process. 
 
Molecular Weight: 853.9 
 
Empirical Formula: C47H51NO14 
 
Description: 
Clear viscous fluid 


 
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b. 
TOXICOLOGY 
 
Human Toxicity: 
 
Dose-limiting toxicity is myelosuppression with reversible granulocytopenia, 
anemia, and thrombocytopenia.  Allergic reactions occur in up to 8% of patients 
receiving paclitaxel as an intravenous infusion over 6 to 24 hours.  These can be 
acute 
anaphylactoid 
reactions 
to 
include 
flushing, 
hypotension, 
and 
bronchospasm; dermatitis and pruritus are also observed.  Hypertension has also 
been seen, and may be related to concomitant medication with dexamethasone.  
Premedication with diphenhydramine, cimetidine, and dexamethasone appears to 
diminish the incidence of these reactions.  Neurotoxicity can include distal painful 
paresthesias.  Rarely, this toxicity has required discontinuation of drug due to 
pain, impairment of fine motor skills, or difficulty ambulating.  Experience to date 
suggests that this neuropathy is reversible.  Rarely, associated forms of 
neurotoxicity have included taste perversion, seizures, and mood changes.  Some 
patients have reported vision abnormalities such as blurred vision, "flashing lights" 
and scintillating scotomata.  Ischemic or infarcted colon, sometimes with 
involvement of other parts of the gastrointestinal tract, has also been seen.  
Patients reporting abdominal discomfort should be monitored closely.  These 
events generally occurred while the patients were severely neutropenic.  They 
may be most consistent with neutropenic enterocolitis (typhlitis).  Although 
increased SGOT, SGPT, bilirubin and alkaline phosphatase, as well as hepatic 
failure and hepatic necrosis have been seen, one patient receiving this drug has 
also experienced hepatic encephalopathy, and two incidences of pancreatitis have 
been noted.  Neuroencephalopathy has also been reported.  Pulmonary toxicities 
that have occurred are pneumonitis and radiation pneumonitis (following 
concomitant paclitaxel and radiation). 
 
Other non-hematologic reactions include:  diarrhea, alopecia, myalgias and 
arthralgias, nausea or vomiting, mucositis (stomatitis and pharyngitis), light-
headedness, myopathy and fatigue.  Less commonly, cardiotoxicity has been 
associated with paclitaxel administration, to include arrhythmias (sinus 
bradycardia, ventricular tachycardia, atrial arrhythmia, and heart block), and 
myocardial infarction.  Skin reactions including erythema, induration, tenderness, 
ulceration, radiation recall, rash and nail changes have occurred including 
discoloration of fingernails and separation from nail bed. 
 
Pregnancy and Lactation:  Paclitaxel may cause fetal harm when administered to 
a pregnant woman.  Paclitaxel has been shown to be embryo- and fetotoxic in rats 
and rabbits and to decrease fertility in rats.  In these studies, paclitaxel was shown 
to result in abortions, decreased corpora lutea, a decrease in implantations and 
live fetuses, and increased resorption and embryo-fetal deaths.  No information is 
available on the excretion of this drug in human milk.  Because many drugs are 
excreted in human milk and because of the potential for serious adverse reactions 
in nursing infants, it is recommended that nursing be discontinued. 
 
c. 
PHARMACOLOGY 
 
Formulation:  Sterile solution containing 6 mg/ml in a 5 ml vial (30 mg per vial) in 
polyoxyethylated castor oil (Cremaphor EL) 50% and dehydrated alcohol, USP, 
50%.  There are also vial sizes of 100 mg and 300 mg. 
 


 
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Solution Preparation:  Paclitaxel is reconstituted by diluting the total dose in 0.9% 
Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP (D5W) to maintain 
a paclitaxel concentration between 0.3 and 1.2 mg/ml.  Paclitaxel must be 
prepared in glass or polyolefin containers due to leaching of diethylhexlphthalate 
(DEHP) plasticizer from polyvinyl chloride (PVC) bags and intravenous tubing by 
the Cremaphor vehicle in which paclitaxel is solubilized.  Each bag/bottle should 
be prepared immediately before administration. 
 
NOTE:  Formation of a small number of fibers in solution (within acceptable limits 
established by the USP Particulate Matter Test for LVPs) has been observed after 
preparation of paclitaxel.  Therefore, in-line filtration is necessary for 
administration of paclitaxel solutions.  In-line filtrations should be accomplished by 
incorporating a hydrophilic, microporous filter of pore size not greater than 0.22 
microns (e.g.:  IVEX-II or IVEX-HP or equivalent) into the IV fluid pathway distal to 
the infusion pump.  Although particulate formation does not indicate loss of drug 
potency, solutions exhibiting excessive particulate matter formation should not be 
used. 
 
Administration of Paclitaxel:  Paclitaxel, at the appropriate dose, will be given as 
an intravenous infusion as specified in the protocol, diluted in 0.9% Sodium 
Chloride Injection, USP, or 5% Dextrose Injection.  Paclitaxel will be administered 
via an infusion control device (pump) using non-PVC tubing and connectors, such 
as the IV administration sets (polyethylene or polyolefin) which are used to infuse 
parenteral nitroglycerin.  Nothing else is to be infused through the line where 
paclitaxel is being administered. 
 
Storage and stability:  The intact vials of paclitaxel should be stored between 2-
25°C.  Based on stability data for Taxol® made from either natural or semi-
synthetic paclitaxel, stored for up to 12 months at 40°C, potency losses were 
within the range of 2.0 to 2.4 percent per year.  Samples stored for up to 3 months 
at 60°C lost potency at rates corresponding to 20 to 40% per year.  Accordingly, 
vials left out in a warm place for a few days should still be satisfactory for use.  All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the 
concentration of drug and the time elapsed after preparation, although when 
prepared as described above, solutions of paclitaxel (0.3-1.2 mg/ml) are physically 
and chemically stable for 27 hours.  Vials will be labeled with a firm expiration 
date. 
 
Supplier:  Paclitaxel is commercially available for purchase by the third party.  This 
drug will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
4.0 
STAGING CRITERIA 
 
Patients must have Stage IV disease as outlined below (AJCC Cancer Staging Manual, 7th 
Edition, 2009): 
 
Stage IV: 
 
 
Any T 
 
 
Any N 
 
 
M1a - Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or 
malignant pleural (or pericardial) effusion.* 
 
 
M1b – Distant metastases 


 
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* Most pleural (or pericardial) effusions associated with lung cancer are due to tumor.  
However, there are a few patients in whom multiple cytopathologic examinations of 
pleural or pericardial fluid are negative for tumor, and the fluid is non-bloody and is not 
an exudate.  When these elements and clinical judgment dictate that the effusion is not 
related to the tumor, the effusion should be excluded as a staging element and the 
patient should be classified as M0. 
 
NOTE:  Any disease that is recurrent after surgery or radiation is classified as Stage IV. 
 


 
 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S0819 Prestudy Form and submit to the Data 
Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be addressed to the 
Data Operations Center in Seattle at 206/652-2267 prior to registration. 
 
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.  
This allows for efficient patient scheduling without exceeding the guidelines.  If Day 7, 14, 28 or 42 falls 
on a weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have histologically or cytologically proven primary non-small cell 
lung cancer (adenocarcinoma, large cell carcinoma, squamous or unspecified).  
Disease must be Stage IV, as defined in Section 4.0.  Disease may be either 
newly diagnosed or recurrent after previous surgery and/or irradiation.  Patients 
with additional lesions in an ipsilateral non-primary lobe without M1a or M1b 
disease will not be considered to have Stage IV disease and are not eligible. 
 
b. 
Patients must have a CT or MRI scan of the brain to evaluate for CNS disease 
within 42 days prior to registration.  Patient must not have brain metastases 
unless: (1) metastases have been treated and have remained controlled for at 
least two weeks following treatment, AND (2) patient has no residual neurological 
dysfunction off corticosteroids for at least 1 day. 
 
c. 
Patients may have measurable or non-measurable disease (see Section 10.1) 
documented by CT or MRI.  The CT from a combined PET/CT may be used to 
document only non-measurable disease unless it is of diagnostic quality as 
defined in Section 10.1a.  Measurable disease must be assessed within 28 days 
prior to registration.  Pleural effusions, ascites and laboratory parameters are not 
acceptable as the only evidence of disease.  Non-measurable disease must be 
assessed within 42 days prior to registration.  All disease must be assessed and 
documented on the Baseline Tumor Assessment Form.  See Sections 15.4 and 
18.6 for guidelines and submission instructions for required central radiology 
review. 
 
d. 
Translational Medicine Studies:  Patients must have tumor tissue available for 
submission that is sufficient for EGFR FISH testing and must agree to submission 
of these specimens as defined in Section 15.0.  Patients must also agree to 
submission of specimens for other translational medicine studies as outlined in 
Section 15.0.  Patient must be offered participation in banking for future research.     


 
  
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
e. 
Patients must not have received prior chemotherapy for any stage non-small cell 
lung cancer. Patients must not have received prior platinum-based chemotherapy 
for any purpose.  Patients must not have received any cetuximab, gefitinib, 
erlotinib or other investigational agents that target the EGFR pathway.  Patients 
must not have received for any purpose prior bevacizumab or other VEGF-related 
agents.  Patients must not have received for any purpose prior chimerized or 
murine monoclonal antibody therapy or have documented presence of human 
anti-mouse antibodies (HAMA). 
 
f. 
Prior radiation is permitted; however, patients must have recovered from all 
associated toxicities at time of registration.  In order to qualify as measurable per 
Section 10.1a, measurable disease must be outside the previous radiation field or 
must have progressed. 
 
g. 
Time from surgical or biopsy procedures is dependent on whether it is planned for 
the patient to receive bevacizumab. 
 
1. 
For patients who are bevacizumab-appropriate AND bevacizumab is 
planned: At least 28 days must have elapsed since major surgery (i.e. 
thoracotomy or VATS resection of lung cancer, open pleural biopsy or 
another major surgical procedure such as abdominal surgery) or 
significant traumatic injury.  Patients must have recovered from all 
associated toxicities at the time of registration. There must be no 
anticipation of need for major surgical procedures during protocol 
treatment. Patients must not have had a core biopsy, mediastinoscopy, 
pleurodesis, VATS pleural biopsy or VATS pericardial window within 14 
days prior to registration. Patients must not have had a percutaneous fine 
needle aspiration (FNA), thoracentesis or central venous access device 
implanted within 7 days prior to registration.  For other surgical 
procedures not listed here, please contact the study coordinators.   
 
2. 
For patients who are bevacizumab-inappropriate or bevacizumab is not 
planned: At least 28 days must have elapsed since major surgery (i.e. 
thoracotomy or VATS resection of lung cancer, open pleural biopsy or 
another major surgical procedure such as abdominal surgery) or 
significant traumatic injury.  Patients must have recovered from all 
associated toxicities at the time of registration. There must be no 
anticipation of need for major surgical procedures during protocol 
treatment. Patients must not have had a core biopsy, mediastinoscopy, 
pleurodesis, VATS pleural biopsy or VATS pericardial window within 7 
days prior to registration. Patients must not have had a percutaneous fine 
needle aspiration (FNA), or thoracentesis within 1 day prior to registration.  
Patients may have had a central venous access device placed at any time 
prior to registration.  For other surgical procedures not listed here, 
please contact the study coordinators.   
 


 
 
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5.2 
Clinical/Laboratory Criteria 
 
a. 
Patients must have an ANC ≥ 1,500/mcl, platelet count ≥ 100,000/mcl, and 
hemoglobin ≥ 9 g/dL obtained within 14 days prior to registration. 
 
b. 
Patients must have a serum creatinine ≤ institutional upper limit of normal (IULN) 
AND calculated or measured creatinine clearance ≥ 50 cc/min using the following 
Cockroft-Gault Formula: 
 
Estimated Creatinine Clearance = (140 - age) X (actual body weight in kg) 
 
72 x serum creatinine 
 
Multiply this number by 0.85 if the patient is a female. 
 
These tests must have been performed within 14 days prior to registration. 
 
c. 
For patients who will be receiving bevacizumab, urine protein must be screened 
by urine analysis for Urine Protein Creatinine (UPC) ratio.  For UPC ratio > 0.5, 
24-hour urine protein must be obtained and the level must be < 1,000 mg for 
patient enrollment.  The urine protein used to calculate the UPC ratio must be 
obtained within 14 days prior to registration.  UPC or 24-hour protein is not 
required for patients who will not receive bevacizumab. 
 
Note: UPC ratio of spot urine is an estimation of the 24-hour 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) x 0.088]/[urine creatinine] – if urine creatinine is reported in 
mmol/L 
 
d. 
Patients must have adequate hepatic function documented by serum bilirubin ≤ 2 
X IULN and either SGOT or SGPT ≤ 2 x IULN within 14 days prior to registration 
(if both SGOT and SGPT are done, both must be ≤ 2 x IULN).  For patients with 
liver metastases, bilirubin and either SGOT or SGPT must be ≤ 5 x IULN.  
 
e. 
All patients must have a Zubrod Performance Status of 0 - 1 (see Section 10.4). 
 
f. 
Patients must not have ≥ Grade 2 symptomatic neuropathy-sensory (NCI 
Common Terminology Criteria Version 3.0).   
 
g. 
Patients must not have documented evidence of acute hepatitis or have an active 
or uncontrolled infection. 
 
h. 
Patients must not have the following:  history (within past 6 months) of CVA, 
myocardial infarction or unstable angina; or at the time of registration, uncontrolled 
hypertension, New York Heart Association Grade 2 or greater congestive heart 
failure (see Appendix 18.3), serious cardiac arrhythmia requiring medication, or 
clinically significant peripheral vascular disease. 
 
i. 
Patients must have no known hypersensitivity to Chinese hamster ovary cell 
products or other recombinant human antibodies [examples include trastuzumab 
(Herceptin) and epoetin alpha]. 
 


 
 
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j. 
Patients must be willing to provide prior smoking history as required on the S0819 
Prestudy Form. 
 
k. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated 
Stage I or II cancer from which the patient is currently in complete remission, or 
any other cancer from which the patient has been disease-free for 5 years. 
 
l. 
Patients must not be pregnant or nursing because of the increased risk of fetal 
harm including fetal death from the chemotherapeutic agents.  Women/men of 
reproductive potential must have agreed to use an effective contraceptive 
method.  A woman is considered to be of "reproductive potential" if she has had 
menses at any time in the preceding 12 consecutive months.  In addition to 
routine 
contraceptive 
methods, 
"effective 
contraception" also 
includes 
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-
effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy 
or bilateral tubal ligation.  However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures. 
 
5.3 
Regulatory Criteria 
 
a. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed 
consent in accordance with institutional and federal guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.2 for OPEN access 
instructions) the treating institution’s identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system.  
 
 
 


 
 
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6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized between Arm 1 (chemotherapy without cetuximab) and Arm 2 
(chemotherapy with cetuximab) using a dynamic balancing algorithm.  (22)  Stratification is based 
on: 
 
6.1 
Bevacizumab–APPROPRIATE Status:  Yes versus No.   
 
Patients are “bevacizumab-INAPPROPRIATE” if ANY ONE of the following apply (Patients 
with a recent history of these conditions should be registered on the study only if the 
condition has resolved or adequately stabilized.):  
 
 
≥ 50% squamous-cell cancer;  
 
history of hemoptysis (1/2 tsp or more per event within the past year);  
 
cavitary pulmonary lesion; 
 
history of documented hemorrhagic diathesis or coagulopathy; patients who have an 
INR > 1.5; 
 
non-healing wound, ulcer or bone fracture, abdominal fistula, GI perforation or intra-
abdominal abscess; 
 
patients receiving therapeutic anticoagulation; regular use of aspirin (> 325 mg per 
day), nonsteroidal anti-inflammatory agents that are known to inhibit platelet function, 
or other agents known to inhibit platelet function; 
 
patients may be placed in the "bevacizumab-INAPPROPRIATE" stratum at their 
request or at the discretion of their treating physician. 
 
If NONE of the above apply, the patient will be stratified into the "bevacizumab-
APPROPRIATE" cohort. 
 
6.2 
Smoking Status 
 
Smoking status:  current or former (no smoking for 1 year or more) versus never (less than 
100 cigarettes lifetime). 
 
6.3 
Stage 
 
Stage:  M1a versus M1b (see Section 4.0). 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact any of the following Study 
Coordinators:  Dr. Herbst at 203/785-6879 or roy.herbst@yale.edu, Dr. Kim at 980/442-3105 or 
edward.kim@carolinashealthcare.org or Dr. Semrad at 916/734-3771 or 
thomas.semrad@ucdmc.ucdavis.edu.  For dosing principles or questions, please refer to the 
SWOG Investigator Letter distributed with Revision #9 or if you have further questions please 
contact the Study Coordinators listed above. 
 
7.1 
Good Medical Practice 
 
The following tests (and/or assessments) are recommended within 28 days prior to 
registration in accordance with good medical practice.  Results of these tests do not 
determine eligibility and minor deviations from normal limits would be acceptable if they do 
not affect patient safety in the clinical judgment of the treating physician.  If there are 
significant deviations in these tests/assessments that could impact patient safety, it 
is highly recommended that the registering investigator discuss the patient with the 
Study Coordinator prior to registration.   


 
 
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a. 
Albumin 
 
b. 
Serum Sodium, Calcium and Magnesium 
 
c. 
LDH 
 
d. 
EKG 
 
e. 
Alkaline Phosphatase 
 
f. 
Bone scan to document bone metastasis, if clinically indicated. 
 
g. 
Patients should not have uncontrolled diabetes mellitus. 
 
h. 
Patients should not have psychological, familial, sociological or geographical 
conditions that do not permit weekly medical follow-up and compliance with the 
study protocol. 
 
i. 
Patients should not have dementia or significantly altered mental status that would 
prohibit the understanding and giving of informed consent. 
 
j. 
Patients should not have any immediate life-threatening complications of their 
malignancies. 
 
k. 
Patients should not have a history of allergic reactions to drugs utilizing the 
vehicle Cremaphor (some anesthetics and muscle relaxants). 
 
7.2 
Pre-medication 
 
a. 
Cetuximab 
 
All patients who will receive cetuximab will be premedicated with: 
 
Agent 
Dose 
Route 
Duration 
 
 
Diphenhydramine 
50 mg 
IV 
prior to the first  
hydrochloride 
 
 
dose of cetuximab 
 
 
Diphenhydramine must be given prior to the first dose of cetuximab in an effort to 
prevent a hypersensitivity reaction.  Premedication is recommended prior to 
subsequent doses, but at the treating physician's discretion, the dose of 
diphenhydramine may be reduced. 
 


 
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b. 
Paclitaxel 
 
All patients should be premedicated with: 
 
Agent 
Dose 
Route 
Duration 
 
 
Dexamethasone 
20 mg* 
PO/IV 
12 and 6 hours 
 
 
 
 
prior to paclitaxel** 
 
Diphenhydramine*** 
50 mg 
IV 
30 minutes prior to 
 
 
 
paclitaxel 
 
plus one of the following 
 
Ranitidine  
50 mg 
IV 
30 minutes prior to 
 
 
paclitaxel 
or 
 
Cimetidine 
300 mg 
IV 
 
 
Famotidine  
20 mg 
PO/IV 
30 minutes prior to  
 
 
 
paclitaxel 
 
 
 
* 20 mg is the dose for each administration.   
** Alternatively, a single intravenous dose of 20 mg may be given 30 minutes 
prior to paclitaxel injection.   
*** If patients received diphenhydramine prior to cetuximab, it does not need to be 
repeated prior to paclitaxel injection. 
 
Dexamethasone (oral) 
 
The investigator should prescribe dexamethasone 4 mg orally every 12 hours for 
6 doses beginning in p.m. on Day 1 of each cycle. 
 
DAY 
AM DOSE 
PM DOSE 
 
Day 1 
-- 
4 mg 
 
Day 2 
4 mg 
4 mg 
 
Day 3 
4 mg 
4 mg 
 
Day 4 
4 mg 
 -- 
 
 
c. 
Carboplatin 
 
Patients should receive antiemetics of the treating physician's choice prior to 
carboplatin administration.  Dose modifications in the antiemetic regimen may be 
made at the discretion of the treating physician as clinically indicated. 
 
7.3 
Treatment 
 
Patients who are bevacizumab-APPROPRIATE will receive bevacizumab (per Arms 1a 
and 2a).  Patients who are bevacizumab-INAPPROPRIATE will not receive bevacizumab 
(per Arms 1b and 2b).  Patients may be placed in the bevacizumab-INAPPROPRIATE 
stratum at their request or at the discretion of their treating physician. 
 


 
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a. 
Arm 1-Chemotherapy Without Cetuximab 
 
Based on the criteria outlined in Section 6.1, patients will be treated as 
"bevacizumab-APPROPRIATE " or "bevacizumab-INAPPROPRIATE". 
 
1. 
Arm 1a-Bevacizumab-APPROPRIATE (see Section 6.1 for definitions) 
 
Treatment consists of up to SIX CYCLES of paclitaxel, carboplatin 
and bevacizumab.  If six cycles are completed and none of the 
criteria in Section 7.8 is met, treatment with bevacizumab will 
continue until one of the criteria in Section 7.8 is met.  ONE CYCLE = 
21 DAYS. 
 
DRUG 
DOSE  
ROUTE 
SCHEDULE 
 
Paclitaxel 
200 mg/m2 
3 hour IV infusion 
q 21 days  
 
 
 
x 6 cycles 
 
Carboplatin 
AUC=6 a 
30 minute IV 
q 21 days  
 
 
infusion 
x 6 cycles  
 
 
immediately 
 
 
 
following 
 
 
paclitaxel 
 
Bevacizumab 
15 mg/kg 
IV infusion 
q 21 days  
 
 
 
over 90 ± 15 
 
(bevacizumab  
 
 
 
minutes b 1 
continues 
 
 
 
hour 
 
beyond 6 cycles 
 
following 
until one of the 
 
carboplatin 
criteria in  
 
 
Section 7.8  
 
 
is met) 
 
a AUC=6 by modified Calvert formula.  Carboplatin is given after 
paclitaxel infusion is completed (see Section 7.5 for Guidelines for 
Carboplatin Administration).  Serum creatinine must be repeated and 
creatinine clearance calculated within 3 days prior to each carboplatin 
dose.  In patients whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl 
must be substituted in the Cockroft-Gault formula to calculate the 
estimated creatinine clearance for carboplatin dosing. This change is 
an addition to the requirement not to exceed a maximum dose of 
carboplatin of 900 mg. (Please see Section 18.2). 
 
b If no adverse reactions occur, the second dose of bevacizumab should 
be given over a minimum of 60 minutes.  If no adverse event occurs, 
third and subsequent doses should be administered over a minimum of 
30 minutes.  Infusions should be run in a volumetric infusion device.  
Infusions should be run over the shortest period that is well-tolerated.  
Also, if the patient tolerates bevacizumab treatment after the first cycle, 
the length of time between the carboplatin and bevacizumab treatment 
may be shortened at the discretion of the treating investigator. 


 
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2. 
Arm 1b-Bevacizumab-INAPPROPRIATE (see Section 6.1 for definitions) 
 
Treatment consists of up to SIX CYCLES of paclitaxel and 
carboplatin if none of the criteria in Section 7.8 is met.  ONE CYCLE 
= 21 DAYS. 
 
DRUG 
DOSE  
ROUTE 
SCHEDULE 
 
Paclitaxel 
200 mg/m2 
3 hour IV infusion 
q 21 days  
 
 
 
X 6 cycles 
 
Carboplatin 
AUC=6 a 
30 minute IV 
q 21 days  
 
 
infusion 
x 6 cycles  
 
 
immediately 
 
 
 
following 
 
 
paclitaxel 
 
 
a AUC=6 by modified Calvert formula.  Carboplatin is given after 
paclitaxel infusion is completed (see Section 7.5 for Guidelines for 
Carboplatin Administration).  Serum creatinine must be repeated and 
creatinine clearance calculated within 3 days prior to carboplatin dose. 
In patients whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be 
substituted in the Cockroft-Gault formula to calculate the estimated 
creatinine clearance for carboplatin dosing. This change is an addition 
to the requirement not to exceed a maximum dose of carboplatin of 
900 mg. (Please see Section 18.2). 
 
b. 
Arm 2-Chemotherapy with Cetuximab 
 
Based on stratification, patients will be treated as "bevacizumab-APPROPRIATE" 
or "bevacizumab-INAPPROPRIATE ". 
 


 
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1. 
Arm 2a-Bevacizumab-APPROPRIATE (see Section 6.1 for definitions) 
 
Treatment consists of up to SIX CYCLES of paclitaxel, carboplatin, 
cetuximab and bevacizumab.  If six cycles are completed and none 
of the criteria in Section 7.8 is met, treatment with cetuximab and 
bevacizumab will continue until one of the criteria in Section 7.8 is 
met.  ONE CYCLE = 21 DAYS. 
 
DRUG 
DOSE  
ROUTE 
SCHEDULE 
 
Cetuximab a 
400 mg/m2 
2 hour IV 
Cycle 1,  
 
(Loading dose) 
infusion 
Week 1 only 
 
 
250 mg/m2 
1 hour IV  
Weekly starting  
 
(Maintenance dose) infusion  
at Week 2  
 
 
 
(cetuximab  
 
 
continues  
 
 
beyond 
 
 
 
6 cycles until  
 
 
 
one of the  
 
 
 
criteria in  
 
 
 
Section 7.8  
 
 
 
is met) 
 
Paclitaxel 
200 mg/m2 
3 hour IV infusion 
q 21 days  
 
 
1 hour following 
starting at  
 
 
cetuximab 
Week 1  
 
 
 
x 6 cycles 
 
Carboplatin 
AUC=6 b 
30 minute IV 
q 21 days  
 
 
infusion 
starting at  
 
 
immediately 
Week 1 
 
 
following 
x 6 cycles 
 
 
paclitaxel 
 
Bevacizumab 
15 mg/kg 
IV infusion 
q 21 days  
 
 
 
over 90 ± 15 
 
starting at  
 
 
 
minutes c 1 
Week 1 
 
 
 
hour 
 
(bevacizumab 
 
following 
continues  
 
carboplatin 
beyond 
 
 
6 cycles until 
 
 
one of the  
 
 
criteria in  
 
 
Section 7.8 
 
 
is met) 
 
a 
An initial dose of cetuximab 400 mg/m2 infused over 2 hours will be given at 
Week 1 only.  Beginning at Week 2, cetuximab will be administered weekly at a 
dose of 250 mg/m2 infused over 1 hour.  Cetuximab may be administered on Day 
1 or Day 2 each cycle when given with chemotherapy, depending on the 
preference of the treating physician.  Despite this option, the order in which 
paclitaxel, carboplatin and bevacizumab are given must remain as stated above.  
Subsequent doses of weekly cetuximab given without chemotherapy should be 
administered as closely to a weekly schedule as possible. During Cycle 1, 
cetuximab must be given prior to paclitaxel, carboplatin and bevacizumab. 


 
 
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b 
AUC=6 by modified Calvert formula.  Carboplatin is given after paclitaxel 
infusion is completed (see Section 7.5 for Guidelines for Carboplatin 
Administration).  Serum creatinine must be repeated and creatinine clearance 
calculated within 3 days prior to each carboplatin dose. In patients whose 
serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-
Gault formula to calculate the estimated creatinine clearance for carboplatin 
dosing. This change is an addition to the requirement not to exceed a 
maximum dose of carboplatin of 900 mg. (Please see Section 18.2). 
c 
If no adverse reactions occur, the second dose of bevacizumab should be 
given over a minimum of 60 minutes.  If no adverse event occurs, third and 
subsequent doses should be administered over a minimum of 30 minutes.  
Infusions should be run in a volumetric infusion device.  Infusions should be 
run over the shortest period that is well-tolerated.  Also, if the patient tolerates 
bevacizumab treatment after the first cycle, the length of time between the 
carboplatin and bevacizumab treatment may be shortened at the discretion of 
the treating investigation. 
 
2. 
Arm 2b-Bevacizumab-INAPPROPRIATE (see Section 6.1 for definitions) 
 
Treatment consists of up to SIX CYCLES of paclitaxel, carboplatin, 
and cetuximab.  If six cycles are completed and none of the criteria 
in Section 7.8 is met, treatment with cetuximab will continue until 
one of the criteria in Section 7.8 is met.  ONE CYCLE = 21 DAYS. 
 
 
DOSE  
ROUTE 
SCHEDULE 
 
Cetuximab a 
400 mg/m2 
2 hour IV 
Cycle 1,  
 
(Loading dose) 
infusion 
Week 1 only 
 
 
250 mg/m2 
1 hour IV  
Weekly starting  
 
(Maintenance 
infusion  
at Week 2  
 
dose) 
 
(cetuximab  
 
 
 
continues beyond 
 
 
 
6 cycles until one  
 
 
 
of the criteria in 
 
 
 
Section 7.8 is met) 
 
Paclitaxel 
200 mg/m2 
3 hour IV 
q 21 days   
 
 
infusion 
starting at 
 
 
1 hour 
Week 1 
 
 
following  
x 6 cycles 
 
 
cetuximab 
 
 
Carboplatin 
AUC=6 b 
30 minute 
q 21 days  
 
 
IV infusion 
starting at 
 
 
immediately 
Week 1 
 
 
following  
x 6 cycles 
 
 
paclitaxel 
 
 
a An initial dose of cetuximab 400 mg/m2 infused over 2 hours will be given at Week 1 only.  
Beginning at Week 2, cetuximab will be administered weekly at a dose of 250 
mg/m2 infused over 1 hour.  Cetuximab may be administered on Day 1 or Day 2 
each cycle when given with chemotherapy, depending on the preference of the 
treating physician. Despite this option, the order in which paclitaxel and 
carboplatin are given must remain as stated above.  Subsequent doses of 
weekly cetuximab given without chemotherapy should be administered as 
closely to weekly as possible. During Cycle 1, cetuximab must be given prior to 
paclitaxel and carboplatin. 


 
 
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b 
AUC=6 by modified Calvert formula.  Carboplatin is given after paclitaxel 
infusion is completed (see Section 7.5 for Guidelines for Carboplatin 
Administration).  Serum creatinine must be repeated and creatinine clearance 
calculated within 3 days prior to each carboplatin dose.  In patients whose 
serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-
Gault formula to calculate the estimated creatinine clearance for carboplatin 
dosing. This change is an addition to the requirement not to exceed a 
maximum dose of carboplatin of 900 mg. (Please see Section 18.2). 
 
7.4 
Precautions 
 
CAUTION:  Allergic reactions may occur during or following cetuximab and paclitaxel 
administration.  As a routine precaution, patients enrolled in this study will be observed 
closely for any potential adverse events by the medical staff from the start of the 
cetuximab infusion to one hour after the end of the infusion in an area with resuscitation 
equipment and other agents (epinephrine, prednisone equivalents, etc.) available.  Vital 
signs (blood pressure, heart rate, respiratory rate and temperature) should be checked 
prior to the administration, midway through the infusion, at the completion of the infusion 
and 1 hour post the infusion.  Should an allergic or infusion reaction to cetuximab occur, 
the patient must be treated according to the best available medical practices.  The 
cetuximab infusion rate should never exceed 5 mL/minute.  The patient's blood pressure 
and heart rate should be monitored during the paclitaxel infusion.  (Frequent vital sign 
monitoring, particularly during the first hour of paclitaxel infusion, is recommended.)  
Epinephrine and diphenhydramine for injection should be readily available during the 
infusion, for emergency treatment of hypersensitivity reactions. 
 
7.5 
Guidelines for Carboplatin Administration 
 
The carboplatin dose (mg) = AUC x (CrCl + 25) where AUC = 6 depending on the dose 
level.  The creatinine clearance will be calculated using a serum creatinine obtained within 
3 days prior to each dose.  Carboplatin dose will be based on GFR* (glomerular filtration 
rate) based on the measurement of creatinine clearance where GFR is calculated using 
the Cockroft-Gault Formula: 
 
CrCI = (140 - age) x actual body weight (kg)** 
72 x serum creatinine*** 
 
Multiply this number by 0.85 if the patient is female. 
 
* 
GFR = calculated creatinine clearance determined using the Cockroft-Gault Formula 
based on age, weight (actual body weight) and serum creatinine. 
 
** Use current (actual) weight.  This should be actual weight but not exceed 140% of 
IBW. 
*** In patients whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be substituted in the 
Cockroft-Gault formula to calculate the estimated creatinine clearance for carboplatin 
dosing. 
 
Please note that:  GFR should not exceed 125 m/min.  Hence, the maximum total 
carboplatin dose should NOT exceed 900 mg. 
 
See Appendix 18.2 for Carboplatin Dosing Worksheet. 
 


 
 
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7.6 
Hematologic Requirements for Day 1 of Each Cycle 
 
Dose delay based on hematologic counts the day of treatment: The ANC count must be ≥ 
1,500/mcl and the platelet count ≥ 100,000/mcl on the day of planned treatment. If this 
recovery is not achieved by the day of treatment, the next cycle will be delayed until 
recovery occurs or a maximum of 2 weeks have passed. If a delay is > 2 weeks based on 
these parameters, discontinue carboplatin and paclitaxel. 
 
7.7 
Supportive Care 
 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, antidiarrheals, analgesics, etc., when appropriate.  
Zoledronic acid is allowed for patients with bone metastases. 
 
7.8 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease based on the investigator's assessment (and as defined in 
Section 10.2d) or symptomatic deterioration (as defined in Section 10.2e).   
 
b. 
Unacceptable toxicity. 
 
c. 
Completion of 6 cycles of treatment for bevacizumab-INAPPROPRIATE patients 
on Arm 1b. 
 
d. 
Treatment delay > 4 weeks for any reason for any agent, except as outlined in 
Section 7.6.  If more than one study drug requires permanent discontinuation 
contact the Study Coordinator. 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.9 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented on the Off Treatment 
Notice. 
 
7.10 
Follow Up Period 
 
All patients will be followed for 3 years after registration or until death, whichever comes 
first. 
 
7.11 
Radiology Review 
 
a. 
To ensure the highest standards and consistency between different centers, all 
scans for disease assessment (baseline, interim, and end of treatment scans) 
must be submitted to the Quality Assurance Review Center (QARC) in 
Providence, RI for centralized review (see Section 15.4).   
 
b. 
Centralized review will be performed by 3 radiology experts.  The scans will 
be submitted to QARC.  QARC will transmit the scans to the reviewers who 
will transmit the results to the SWOG Statistical Center. 
 
c. 
Details of submission of scans to QARC for centralized review and on the central 
review process are listed in Section 15.4 and Appendix 18.6.   
 
 


 
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8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events (CTCAE) 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 
will be utilized for SAE reporting only. The CTCAE Version 4.0 is identified and 
located at the CTEP website at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate treatment areas should have access to a copy of the CTCAE Version 
4.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 3.0 for routine toxicity reporting. A copy 
of the CTCAE Version 3.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a 
copy of the CTCAE Version 3.0. 
 
8.2 
General Dose Modifications 
 
Dose adjustments of carboplatin, paclitaxel, cetuximab and bevacizumab will be made 
based on the occurrence and extent of toxicity. 
 
NOTE:  ALL DOSE REDUCTIONS ARE PERMANENT.  THERE WILL BE NO DOSE 
RE-ESCALATIONS AFTER A DOSE REDUCTION, except as specifically described in 
Section 8.6 in conjunction with the use of G-CSF. 
 
a. 
Carboplatin, paclitaxel and bevacizumab therapy will not be held for cetuximab 
related toxicities. 
 
b. 
Cetuximab therapy will not be held for carboplatin, paclitaxel or bevacizumab 
related toxicities. 
 
c. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
8.3 
Dose Modifications for Carboplatin and Paclitaxel  
 
Dose Level 
Carboplatin 
Paclitaxel 
 
(AUC) 
(mg/m2) 
 
(Starting Dose) 
 
0 
6 
200 
 
 
-1 
 
5 
175 
 
 
-2 
 
4 
150 
 
 
-3* 
3 
125 
 
 
* Dose reductions beyond this level are not permitted. 
 


 
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a. 
Hematologic - Carboplatin and Paclitaxel  
 
1. 
Neutropenia:  The following dose adjustments are based on either Day 1 
CBC or interim CBC if done. Repeat dose reduction for each subsequent 
occurrence: 
 
Absolute Neutrophil 
Carboplatin 
Paclitaxel 
Count (/mcl) 
(AUC) 
Dose Level 
 
≥ 500 
 
No change  
No change 
 
< 500 
 
No change  
Reduce by 1  
or febrile  
 
 
dose level * 
neutropenia 
 
 
* Patients with ANC < 500/mcl or febrile neutropenia despite two dose 
level reductions of paclitaxel, should have one dose level reduction of 
carboplatin, in addition to a third dose level reduction of paclitaxel. 
 
2. 
Thrombocytopenia:  The following dose adjustments are based on the 
hematological nadir of the preceding treatment cycle. Repeat dose 
reduction for each subsequent occurrence: 
 
Platelet 
Carboplatin 
Paclitaxel 
Count (/mcl) 
(AUC) 
Dose Level 
 
≥ 50,000  
No change  
No change 
 
< 50,000 
Reduce by 1 
No change 
 
dose level * 
 
* For example, if current AUC is 6, reduce dose to AUC 5.  Patients with 
platelets < 50,000/mcl despite two dose level reductions of carboplatin, 
should have one dose level reduction of paclitaxel, in addition to a third 
dose level reduction of carboplatin. 
 
b. 
Hepatic - Paclitaxel 
 
The following paclitaxel dose adjustments are based on SGOT or SGPT and 
bilirubin serum levels and (after the first cycle of treatment) should be obtained 
within seven days prior to treatment. 
 
SGOT or SGPT 
Bilirubin 
Paclitaxel 
 
 
Grade 0 - 1 
and 
Grade 0 - 2 
No change 
 
Grade 2 - 4 
or 
Grade 3 - 4 
HOLD* 
 
 
 
 
 
* If recovery of toxicity exceeds two weeks, discontinue carboplatin and paclitaxel.  
If recovery of toxicity occurs within two weeks (< Grade 2), resume treatment 
with one dose level reduction of paclitaxel. 
 


 
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c. 
Arthralgia/Myalgia - Paclitaxel  
 
The following dose adjustments are based on the worst toxicity grade experience 
of arthralgia/myalgia of any preceding treatment cycle. 
 
Arthralgia/Myalgia 
Paclitaxel 
 
Grade 0 - 2 
No Change 
 
Grade 3 
- 1 dose level ** 
 
Grade 4 
- 2 dose levels** 
 
**  Reduce if post-medication dexamethasone (Section 7.2b) was incorporated in 
regimen.  If no post-chemotherapy dexamethasone was administered, then 
prior to making any dose level reduction, the treating physician must add the 
regimen described in Section 7.2b to subsequent courses. 
 
d. 
Neuropathy:  Motor/Sensory - Carboplatin and Paclitaxel  
 
The following dose adjustments are based on the worst toxicity grade experience 
of neuropathy - motor/sensory of any preceding treatment cycle. 
 
Neuropathy - motor/sensory 
Carboplatin and Paclitaxel 
 
Grade 0 - 1 
No Change 
 
 
 
Grade 2 - 3 
HOLD BOTH DRUGS  
(until resolution to ≤ Grade 1); resume 
at a one dose level reduction for both 
drugs 
 
Grade 4REMOVE 
PATIENT 
FROM 
PAC-LITAXEL AND CARBOPLATIN 
TREATMENT 
 
 
e. 
Cardiac Toxicity - Carboplatin and Paclitaxel  
 
If a patient develops chest pain or arrhythmia during the infusion, the infusion 
should be stopped.  Manage any arrhythmias according to standard practice.  
Patients who experience chest pain during paclitaxel infusion should not restart 
paclitaxel until a cardiac ischemic event has been ruled out.  Patients will be 
removed from paclitaxel and carboplatin treatment in cases of symptomatic 
arrhythmias or AV block (except first degree) or other heart block.  In case of first 
degree AV block, patient may continue paclitaxel infusion with continuous cardiac 
monitoring during the infusion, at the discretion of the treating physician. 
 
f. 
Hypersensitivity Reactions - Paclitaxel 
 
Caution:  Patients who have a mild to moderate hypersensitivity reaction should 
be rechallenged, but careful attention to prophylaxis and bedside monitoring of 
vital signs is recommended. 
 


 
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For moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest 
discomfort), stop the infusion.  Give intravenous diphenhydramine 25 mg and 
intravenous dexamethasone 10 mg.  After recovery of symptoms, resume infusion 
at a low rate, 20 mg/hr for 15 minutes.  If no further symptoms, resume at full dose 
rate until infusion is complete.  If symptoms recur, stop infusion.  The patient 
should receive no additional paclitaxel for that cycle, but may be retreated after 
discussion with the Study Coordinator.    
 
For severe life threatening symptoms (e.g., hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilator therapy, generalized 
urticaria), 
stop 
the 
infusion. 
 
Give 
intravenous 
diphenhydramine and 
dexamethasone as above.  Add epinephrine or bronchodilators if indicated.  If 
wheezing is present that is not responsive to administration of 0.35 cc of 
nebulized salbutamol solution (or equivalent), epinephrine is recommended.  The 
patient will be taken off paclitaxel treatment.   
 
g. 
Hyperglycemia - Carboplatin and Paclitaxel  
 
Diabetic patients will occasionally experience Grade 3 - 4 hyperglycemic reaction 
to premedication: 
 
Hyperglycemia 
Carboplatin and Paclitaxel 
 
Grade 3 
Continue with planned treatment, if possible,  
(> 250 - 500 mg/dl) 
and give appropriate dose(s) of insulin during 
chemotherapy infusion. 
 
Grade 4  
Hold both drugs until hyperglycemia resolves.* 
(> 500 mg/dl or ketoacidosis) 
 
 
 
 
* If indicated, subsequent treatment may be continued with insulin or appropriate 
oral agent to prevent Grade 4 hyperglycemia in subsequent treatment courses. 
 
h. 
Renal - Carboplatin  
 
There will be no dose modifications of paclitaxel dose based on renal toxicity.  If 
creatinine is greater than IULN, hold carboplatin until ≥ 50 cc/minute then 
recalculate dose based on Calvert Formula (Section 7.5). 
 
8.4 
Dose Modifications for Cetuximab 
 
Dose Level  
Cetuximab (mg/m2) 
 
 
(Starting Dose)* 
 
0 
250 
 
 
-1 
200 
 
 
-2 
150 
 
* The cetuximab dose levels indicated pertain to administration of a maintenance dose.  
If toxicities occur with the loading dose, cetuximab should be held until resolution (as 
defined throughout Section 8.4), then begun at the starting dose of 250 mg/m2. There 
will be no cetuximab dose level reductions below a weekly dose of 150 mg/m2.   
 


 
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a. 
Dermatologic Toxicities 
 
Patients developing dermatologic toxicities while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae and 
appropriate treatment of these symptoms should be initiated.  Dose modifications 
of any future cetuximab infusions should be instituted in case of severe acneiform 
rash (Grade 3). 
 
For the treatment of rash, it is recommended that patients be started on a 
tetracycline (e.g., tetracycline 500 mg BID; minocycline 100 mg BID; or 
doxycycline 100 mg BID) and clindamycin topical lotion BID within 5 days after the 
start of therapy.  Treatment will be discontinued or modified following completion 
of cetuximab therapy or if the treating physician feels it is in the patient’s best 
interest.  (See Appendix 18.4.) 
 
Dry skin will be noted in most patients receiving cetuximab.  This should be 
treated with an emollient twice daily. 
 
With prolonged use of cetuximab, some patients may develop paronychial 
inflammation of the fingers and toes or fissuring of the fingertips.  In general, good 
hygiene with appropriate local measures such as soaks in aluminum acetate 
(Burow’s) solution BID-QID will prevent secondary infection.  Symptom relief may 
be achieved with standard bandages or with the application of liquid bandages 
(cyanoacrylate preparations such as Band-Aid Liquid Bandage). 
 
Toxicity and Grade 
Dose Modification 
 
Rash:  
acne/acneiform 
 
No dose modification is required for Grade 1 or 2 rash. 
Treatment with topical and/or oral antibiotics should be 
considered at the discretion of the treating physician. 
Topical corticosteroids are not recommended.  For 
Grade 2 rash that is unacceptable to the patient for 
symptomatic reasons, cetuximab may be held until 
resolution to  Grade 1 for up to 4 weeks. 
 
1st Occurrence
Delay cetuximab treatment for 1 to 2 weeks.  If toxicity 
resolves to  Grade 2, treatment may resume without 
change in dose level.  If toxicity does not resolve to ≤
Grade 2 after 4 weeks, discontinue cetuximab. 
 
2nd Occurrence 
Delay cetuximab treatment for 1 to 2 weeks.  If toxicity 
resolves to  Grade 2, treatment should be re-initiated 
at 200 mg/m2.  If toxicity does not resolve to ≤ Grade 2 
after 4 weeks, discontinue cetuximab. 
 
3rd Occurrence 
Delay cetuximab therapy for 1 to 2 weeks.  If toxicity 
resolves to  Grade 2, treatment should be re-initiated 
at 150 mg/m2.  If toxicity does not resolve to ≤ Grade 2 
after 4 weeks, discontinue cetuximab. 
 
4th Occurrence 
Discontinue cetuximab. 
 
 


 
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b. 
Infusion Reactions 
 
Toxicity and Grade 
Dose Modification 
 
 
Mild to moderate (Grade 1 or 2) infusion reactions are 
managed by slowing the infusion rate for cetuximab 
and by employing prophylactic use of antihistamine 
medications for subsequent doses.  If the patient 
experiences Grade 1 or 2 infusion reaction, the infusion 
rate should be permanently reduced by 50%.* 
Acetaminophen or a non-steroidal anti-inflammatory 
drug (NSAID) may be administered prior to subsequent 
cetuximab infusions, if not otherwise contraindicated in 
patients. 
 
Severe infusion reactions, characterized by airway 
obstruction 
(bronchospasm, 
stridor, 
hoarseness), 
urticaria 
and/or 
hypotension 
require 
immediate 
interruption of cetuximab infusion and permanent 
discontinuation from further cetuximab.  Appropriate 
medical therapy including epinephrine, corticosteroids, 
intravenous antihistamines, bronchodilators and oxygen 
should be available for use in the treatment of such 
reactions.  Patients should be carefully observed until the 
complete resolution of all signs and symptoms. 
* In the event of isolated drug fever, the treating physician must use clinical 
judgment to determine if the fever is related to cetuximab or to an infectious 
etiology.  If a patient experiences isolated drug fever, for the next dose pre-treat 
with acetaminophen or non-steroidal anti-inflammatory agent (physician 
discretion), repeat antipyretic dose 6 and 12 hours after cetuximab infusion.  
The infusion rate will remain unchanged for subsequent doses. 
 
c. 
Pulmonary Toxicities 
 
Toxicity and Grade 
Dose Modification 
 
 
 
Hold cetuximab.  If not resolved within 4 weeks, 
discontinue protocol treatment.  If interstitial lung 
disease (ILD) is confirmed, cetuximab should be 
discontinued 
and 
patient 
should 
be 
treated 
appropriately.
 
In the event of acute onset (Grade  2) or worsening pulmonary symptoms that 
are not thought to be related to underlying cancer, cetuximab therapy should be 
interrupted and a prompt investigation of these symptoms should occur. 
Cetuximab re-treatment should not occur until these symptoms have resolved to 
Grade 1.  If interstitial lung disease is confirmed, cetuximab should be 
discontinued and the patient should be treated appropriately. 
 
d. 
Hypomagnesemia 
 
In the event of hypomagnesemia, more frequent monitoring and magnesium 
repletion should be instituted as per routine clinical practice.  Cetuximab will be 
held for Grade 3-4 hypomagnesemia until recovery to Grade 2 or less. 
 


 
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e. 
For any other medically concerning event ≥ Grade 2, please contact any of the 
following Study Coordinators: Dr. Herbst at 203/785-6879 or roy.herbst@yale.edu, 
Dr. Kim at 980/442-3105 or edward.kim@carolinashealthcare.org or Dr. Semrad 
at 916/734-3771 or thomas.semrad@ucdmc.ucdavis.edu. 
 
8.5 
Dose Modifications for Bevacizumab 
 
There are no reductions for bevacizumab dose levels, just dose delays. If adverse events 
occur that require holding bevacizumab, the dose will remain the same once treatment 
resumes.  Adverse events requiring delays or permanent discontinuation of bevacizumab 
are outlined below.   
  
Patients who require discontinuation of bevacizumab for toxicity may continue to receive 
the other treatment agents. 
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE v3.0 
Grade 
Action to be Taken 
Allergic reactions,  
 
or  
 
Acute infusional 
reactions/ cytokine 
release syndrome  
 
Grade 1-3
 
 
If infusion-related or allergic reactions occur, 
premeds should be given with the next dose, 
and infusion time must not be reduced for the 
subsequent infusion.  For patients with 
Grade 3 reactions, bevacizumab infusion 
should be stopped and not restarted on the 
same day.  At the physicians’ discretion, 
bevacizumab may be permanently 
discontinued or re-instituted with premeds 
and at a rate of 90 ± 15 min.  If bevacizumab 
is re-instituted, the patient should be 
closely monitored for a duration 
comparable to or longer than the duration 
of the previous reactions.   
Grade 4
Discontinue bevacizumab 
Arterial Thrombosis 
 Cardiac ischemia/ 
infarction 
 CNS ischemia (TIA, 
CVA) 
 any peripheral or 
visceral arterial 
ischemia/thrombosis 
Grade 2 (if new or 
worsened since 
bevacizumab 
therapy) 
Discontinue bevacizumab 
Grade 3-4
Discontinue bevacizumab 
Reversible Posterior
Leukoenceph-
alopathy 
Syndrome 
Bevacizumab should be held in patients with 
symptoms/signs suggestive of RPLS, pending 
work-up and management, including control 
of blood pressure.  Bevacizumab should be 
discontinued upon diagnosis of RPLS. 
Venous Thrombosis
 
≥ Grade 3
Discontinue bevacizumab 
 


 
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Hypertension 
 
The dose of bevacizumab should be held for resting SBP > 150 or resting DBP > 100 
at the time of infusion.  Dose should also be held for symptomatic hypertension 
regardless of grade or blood pressure level.  Dose may be held for up to 4 weeks. 
 
No dose modifications for Grade 1-2 events.
Grade 3 
Medications should be used for blood pressure control.  Ideal 
goal for blood pressure is < 140/80.  If a new anti-hypertensive 
is to be added, the choice of drug is at the discretion of treating 
physician.  Prior experience with bevacizumab-associated 
hypertension 
among 
carcinoid 
patients 
suggested 
dihydrophyridine calcium channel blockers and alpha adrenergic 
vasodilators were effective.  In general, the dose of agents 
should be maximized prior to changing or adding new agents.  
Record any new anti-hypertensive added and whether blood 
pressure was adequately controlled. 
Recommended anti-hypertensives: 
 
nifidipine (Procardia XL®, Adalat CC®) 30 to 90 mg q day 
 
nicardipine (Cardine SR®) 30 to 60 mg BID 
 
terazosin (Hytrin®) 2 to 10 mg per day 
 
doxazosin (Cardura®) 1 to 2 mg q day 
 
If HTN cannot be controlled with medications, remove patient 
from protocol treatment. 
Grade 4 
e patient from protocol treatment
Proteinuria 
 
[Proteinuria should be monitored by urine analysis for urine 
protein creatinine (UPC) ratio prior to every other dose of 
bevacizumab.] 
UPC ratio < 3.5
Continue bevacizumab 
UPC ratio ≥ 3.5
Hold bevacizumab until UPC recovers to < 
3.5.  If bevacizumab is held for > 8 weeks due 
to proteinuria, discontinue bevacizumab. 
Grade 4 or 
nephrotic 
syndrome
Discontinue bevacizumab 
 
Wound dehiscence requiring medical 
or surgical intervention
Discontinue bevacizumab 
GI perforation, GI  leak or fistula
Discontinue bevacizumab 
Hemoptysis 
≥ Grade 2
Discontinue bevacizumab 


 
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Hemorrhage 
Grade 3
 

Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
 For patients not on full-dose 
anticoagulation, 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 
bevacizumab. 
 
Grade 4
Discontinue bevacizumab 
Other clinically 
significant AEs 
attributable to 
bevacizumab 
(except controlled 
nausea/vomiting) 
Grade 3
Hold bevacizumab for up to 4 weeks until 
symptoms resolve to ≤ Grade 1 
 
Grade 4

Discontinue bevacizumab 
 
Upon consultation with the Study 
Coordinator, resumption of bevacizumab 
may be considered if a patient is benefiting 
from therapy, and the Grade 4 toxicity is 
transient, has recovered to ≤ Grade 1 
within 4 weeks and is unlikely to recur with 
retreatment. 
 
8.6 
G-CSF Usage 
 
G-CSF (Amgen) has been licensed by the Food and Drug Administration for the 
prevention of chemotherapy induced neutropenia and may be used according to clinical 
practice guidelines.  It may be used for patients who develop Grade 3 - 4 neutropenia.  For 
patients who experience Grade 3 or 4 neutropenia or develop neutropenic fever between 
cycles of chemotherapy, G-CSF may be added to all subsequent cycles of chemotherapy.  
G-CSF is commercially available and should be purchased through third party 
mechanisms.  The NCI will not provide G-CSF for this study. 
 
If G-CSF is used, it is recommended that it be used in the following manner: 
 
If a patient develops neutropenia following chemotherapy, all dose modifications outlined 
in the protocol will be followed according to the original protocol.  However, G-CSF will be 
added to all subsequent cycles of chemotherapy, unless there is clinical suspicion that the 
neutropenia was due to an unrelated medical condition and not due to the chemotherapy. 
 
If the patient maintains an ANC of ≥ 1,000/mm3 throughout the initial cycle of G-CSF 
supported chemotherapy, then the next cycle of chemotherapy may be increased back to 
the original dose level with the continued support of the G-CSF.  No dose escalations 
above the original dose level should be performed on patients taking G-CSF. 
 


 
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G-CSF will be given at a dose of 5 mcg/kg/d subcutaneously beginning 24 hours after 
completion of chemotherapy and continuing until the ANC exceeds 1,000/mcl on two 
successive determinations.  Doses may be rounded off to the nearest vial size (300 mcg 
and 480 mcg vials).  G-CSF should be discontinued at least 24 hours before the next 
chemotherapy dose.  While the patient is receiving G-CSF, the CBC should be monitored 
at least twice a week (more frequently if clinically indicated). 
 
NOTE:  Neulasta™ (pegfilgrastim) is allowed in the place of G-CSF.  The dose is 6 mg 
given once, 24 hours after chemotherapy.  While the patient is receiving Neulasta™, the 
CBC should be monitored weekly. 
 
The use of G-CSF or pegfilgrastim must be documented on the S0819 Treatment Form. 
 
8.7 
G-CSF Dose Modifications 
 
Dose adjustments for toxicities associated with G-CSF (bone pain, splenomegaly, 
abnormalities in uric acid concentrations, LDH and alkaline phosphatase, transient 
elevations of serum creatinine and aminotransferase activity)   
 
Dose modifications for G-CSF toxicity should only be initiated if symptomatic control of the 
toxicity fails (i.e., analgesics such as acetaminophen or acetaminophen with codeine for 
myalgias or bone pain, etc.). 
 
Toxicity Grade 
Dose Adjustment 
 
 
Grade 0 - 1 
No change 
 
Grade 2 
Decrease G-CSF to 3 mcg/kg/d 
 
Grade 3 - 4 
Discontinue G-CSF 
 
 
 
 
8.8 
Dose Modifications for Non-Hematologic Toxicity 
 
In the event of any other (except nausea and vomiting) Grade 3 or 4 non-hematologic 
toxicity not discussed above, hold all protocol treatment and discuss with one of the 
Study Coordinators listed in Section 8.9.  
 
8.9 
Dose Modification Contacts 
 
For treatment or dose modification related questions, please contact any of the following 
Study Coordinators:  Dr. Herbst at 203/785-6879 or roy.herbst@yale.edu, Dr. Kim at 
980/442-3105 or edward.kim@carolinashealthcare.org or Dr. Semrad at 916/734-3771 or 
thomas.semrad@ucdmc.ucdavis.edu.  
 
8.10 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
 
9.0 
STUDY CALENDAR 
 
 


 
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9.1 
Study Calendar - ARM 1a - Chemotherapy plus Bevacizumab without Cetuximab 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √ 
Cont’d TX
√ ≠ 
Off TX F/U
Prior to Prog
ƒ ¶ 
Off TX F/U
After Prog 
ƒ 
REQUIRED STUDIES 
PRE 
W W W
W
W W
W
W W
W
W
W
W
W W 
W
W
W
W
W
W
 
 
 
STUDY 1 
2
3
4 
5
6
7 
8
9
10
11 12
13
14 15 16
17 18
19
20 21
 
 
PHYSICAL 
 
 
 
 
H&P 
X 
 
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X 
X 
Wt & PS 
X 
 
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X 
X 
Disease 
Assessment ¶ 
 
X 
 
 
 
 
 
 
 
X ß
 
 
 
 
 
 
X ß
 
 
 
 
 
 
X ß
 
 
 
X 
 
Toxicity 
Notation 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
X
LABORATORY 
 
 
 
 
CBC/Diff/Platelets £ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Serum Creatinine ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Calc or Meas CrCL ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
 
 
 
X 
X 
UPC (Urine Protein 
Creatinine) Ratio π 
 
X 
 
 
 
 
X
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X 
 
Total Bilirubin § 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
SGOT or SGPT § 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Alk Phos ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
LDH ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Serum Sodium, Calcium 
& Magnesium † ∞ 
 
 
X 
 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
X 
 
X 
SPECIMEN/IMAGE 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Submission * 
X 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tissue Submission * 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission & 
X 
 
 
 
 
 
 
X
 
 
 
 
 
X
 
 
 
 
 
X
 
 
X 
 
 
Calendar continued on next page. Click here for footnotes.


 
 
S0819 
 
 
Page 64 
 
 
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9.1 (contd.) 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √ 
Cont’d TX
√ ≠ 
Off TX F/U
Prior to Prog
ƒ ¶ 
Off TX F/U
After Prog 
ƒ 
REQUIRED STUDIES 
PRE 
W W W W W W
W
W
W
W
W
W
W
W
W W W
W 
W
W
W
 
 
 
STUDY 1 
2 
3
4
5
6
7
8
9
10
11 12
13
14
15 16 17
18
19
20 21
SCANS 
 
 
 
 
 
CT or MRI for Disease 
Assessment ¶ 
X 
 
 
 
 
 
 
X ß
 
 
 
 
 
X ß
 
 
 
 
 
X ß
 
 
 
X 
 
Brain CT/MRI 
X 
 
 
 
 
Bone Scan Ω 
X 
 
 
 
 
EKG ¥ 
X 
 
 
 
 
TREATMENT ∆ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carboplatin 
 
X 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
 
 
 
 
 
Paclitaxel 
 
X 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
 
 
 
 
 
Bevacizumab √ % 
 
X 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X √
 
 
 
 
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 14.0. 
 
∞ 
Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good 
Medical Practice (see Section 7.1). 
† 
In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. 
¶ 
CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression.  After 9 
months from registration, the frequency of this scan may be reduced to every 3 months until disease progression. 
¤ 
Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. 
* 
See Section 15.0. 
& 
Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. 
§ 
SGOT or SGPT and bilirubin is required within 7 days prior to each dose of paclitaxel/carboplatin. 
Ω  This test is required prestudy for Good Medical Practice only if clinically indicated.  It is recommended to be performed during treatment if clinically indicated. 
£ 
CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. 
√ 
After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, bevacizumab will be continued until one of the criteria in Section 7.8 is 
met.  Patients who are bevacizumab inappropriate are removed from protocol treatment at this time. 
ƒ 
After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years 
from the date of registration. 
∆ 
See Sections 7.2 and 7.3. 
% 
Bevacizumab will be given only if patient is determined to be bevacizumab-appropriate. 
π 
After beginning treatment, UPC ratio required with alternate cycles only for patients who are receiving bevacizumab. 
ß 
To be performed within 7 days prior to starting cycle. 
¥ 
This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). 
≠ 
During continued treatment, items marked under physical and laboratory should be performed at every subsequent bevacizumab treatment (every 3 weeks).  
Disease assessments and image submission are to take place every 6 weeks. 


 
 
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9.2 
ARM 1b - Chemotherapy without Cetuximab 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Off TX F/U 
Prior to Prog ƒ ¶
Off TX F/U
After Prog ƒ
REQUIRED STUDIES 
PRE 
W W W
W
W W
W
W W
W
W
W
W 
W W
W
W
W
 
STUDY
1
2
3
4
5
6
7
8
9
10
11 12
13 14 15
16
17 18
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P 
X 
 
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß 
 
 
X ß
 
 
X 
X 
Wt & PS 
X 
 
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß 
 
 
X ß
 
 
X 
X 
Disease 
Assessment ¶ 
 
X 
 
 
 
 
 
 
 
X ß
 
 
 
 
 
 
X ß 
 
 
 
 
 
 
X 
 
Toxicity 
Notation 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X 
 
 
 
X
 
 
 
X
 
X
LABORATORY 
 
 
 
CBC/Diff/Platelets £ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
Serum Creatinine ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
Calc or Meas CrCL ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
Total Bilirubin § 
X 
X
X
X
X 
 
X
X
X
SGOT or SGPT § 
X 
X
X
X
X 
 
X
X
X
Alk Phos ∞ 
X 
X
X
X
X 
 
X
X
X
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
LDH ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
Serum Sodium, Calcium 
& Magnesium † ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
X 
SPECIMEN/IMAGE 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Submission * 
X 
X
 
 
X
X
Tissue Submission * 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission & 
X 
 
 
 
 
 
 
X
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Calendar continued on next page.  Click here for footnotes


 
 
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Version Date 10/3/16 
 
 
 
 
9.2 (contd.) 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √
Off TX F/U 
Prior to Prog ƒ ¶
Off TX F/U
After Prog ƒ
REQUIRED STUDIES 
PRE 
W W W W W W
W
W W
W
W
W
W 
W W
W
W
W
 
STUDY
1
2
3
4
5
6
7
8
9
10 11 12
13 14 15 16 17 18
SCANS 
 
 
 
CT or MRI for Disease 
Assessment ¶ 
X 
 
 
 
 
 
 
X ß
 
 
 
 
 
X ß 
 
 
 
 
 
 
X
 
Brain CT/MRI 
X 
 
 
Bone Scan Ω 
X 
 
 
EKG ¥ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT ∆ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carboplatin 
 
X
X
X
X
X 
 
 
X
Paclitaxel 
 
X
X
X
X
X 
 
 
X
 
Note:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 14.0. 
 
∞ Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with 
Good Medical Practice (see Section 7.1). 
† In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. 
¶ CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression.  
After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression. 
¤ Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. 
* 
See Section 15.0. 
& Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. 
§ SGOT or SGPT and bilirubin are required within 7 days prior to each dose of paclitaxel/carboplatin. 
Ω  This test is required prestudy for Good Medical Practice only if clinically indicated.  It is recommended to be performed during treatment if clinically 
indicated. 
£ CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. 
ƒ After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 
years from the date of registration. 
∆ See Sections 7.2 and 7.3. 
ß To be performed within 7 days prior to starting cycle. 
¥ This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). 
 
 


 
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9.3 
ARM 2a - Chemotherapy plus Bevacizumab with Cetuximab 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √ 
Cont’d TX
√ ≠
Off TX F/U 
Prior to Prog ƒ
Off TX F/U
After Prog ƒ
REQUIRED STUDIES 
PRE 
W W W
W
W W
W
W W
W
W
W
W
W W 
W
W
W
W
W
W
 
STUDY 1 
2
3
4
5
6
7
8
9
10
11 12
13
14 15 16
17 18
19
20 21
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H&P 
X 
 
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X ß
 
 
X 
X 
Vital Signs Only $ 
 
X X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X
X
X 
X 
Wt & PS 
X 
 
X ß
X ß
X ß
X ß
 
X ß
X ß
X
X
Disease 
Assessment ¶ 
 
X 
 
 
 
 
 
 
 
X ß
 
 
 
 
 
 
X ß
 
 
 
 
 
 
X ß
 
 
 
X 
 
Toxicity 
Notation $ 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
 
 
X
 
X
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Diff/Platelets £ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Serum Creatinine ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Calc or Meas CrCL ¤ 
X 
 
X
X
X
X
 
X
X
X
UPC (Urine Protein 
Creatinine) Ratio π 
 
X 
 
 
 
 
X
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
X 
 
Total Bilirubin § 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
SGOT or SGPT § 
X 
 
X
X
X
X
 
X
X
X
X
Alk Phos ∞ 
X 
 
X
X
X
X
 
X
X
X
X
INR 
X 
 
 
Albumin ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
LDH ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
X 
Serum Sodium, Calcium 
& Magnesium † ∞ 
 
 
X 
 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
X 
 
X 
SPECIMEN/IMAGE 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Submission * 
X 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tissue Submission * 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image Submission & 
X 
 
X
X
 
X
X
Calendar continued on next page.  Click here for footnotes. 


 
 
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Version Date 10/3/16 
 
 
 
 
9.3 (contd.) 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √
Cont’d TX
√ ≠ 
Off TX F/U 
Prior to Prog ƒ ¶
Off TX F/U
After Prog ƒ
REQUIRED STUDIES 
PRE 
W W W W W W
W
W W
W
W
W
W
W
W W W
W
W
W
W
 
STUDY 1 
2
3
4
5
6
7
8
9
10 11 12
13
14 15 16 17 18
19
20 21
SCANS 
 
 
 
 
CT or MRI for Disease 
Assessment ¶ 
X 
 
 
 
 
 
 
X ß
 
 
 
 
 
X ß
 
 
 
 
 
X ß
 
 
 
X
 
Brain CT/MRI 
X 
 
 
 
Bone Scan Ω 
X 
 
 
 
EKG ¥ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT ∆ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carboplatin 
 
X 
 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
 
 
 
 
 
Paclitaxel 
 
X 
X
X
X
X
 
X 
Cetuximab √ 
 
X X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X√
X
X
Bevacizumab √ % 
 
X 
X
X
X
X
 
X 
X √
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are 
found in Section 14.0. 
 
Click here for footnotes. 
 


 
 
S0819 
 
 
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Version Date 10/3/16 
 
 
 
 
Calendar 9.3 Footnotes 
 
∞ 
Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good 
Medical Practice (see Section 7.1). 
† 
In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice. 
¶ 
CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1b must be repeated every 6 weeks until disease progression.  After 9 
months from registration, the frequency of this scan may be reduced to every 3 months until disease progression. 
¤ 
Calculated CrCl based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. 
* 
See Section 15.0. 
& 
Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. 
§ 
SGOT or SGPT and bilirubin are required within 7 days prior to each dose of paclitaxel/carboplatin. 
Ω  This test is required prestudy for Good Medical Practice only if clinically indicated.  It is recommended to be performed during treatment if clinically indicated. 
£ 
CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6. 
√ 
After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, bevacizumab and cetuximab will be continued until one of the criteria 
in Section 7.8 is met. 
ƒ 
After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years 
from the date of registration. 
∆ 
See Sections 7.2 and 7.3. 
$ 
Patients will have vital signs taken (before, during and after treatment) and will be evaluated for toxicities at each visit during cetuximab treatment (see Section 
3.3c – “Administration of Cetuximab”). 
% 
Bevacizumab will be given only if patient is determined to be bevacizumab-appropriate. 
π 
After beginning treatment, UPC ratio required with alternate cycles only for patients who are receiving bevacizumab. 
ß 
To be performed within 7 days prior to starting cycle. 
¥ 
This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). 
≠ 
During continued treatment, items marked under physical and laboratory should be performed at every subsequent bevacizumab treatment (every 3 weeks).  
Vital signs and toxicity notation should still be continued on a weekly basis according to the footnote labeled “$”.  Disease assessments and image submission 
are to take place every 6 weeks. 
 


 
 
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Version Date 10/3/16 
 
 
 
9.4 
ARM 2b - Chemotherapy with Cetuximab 
Calendar continued on next page. Click here for footnotes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Off  Tx 
F/U Prior 
To Prog   ƒ
Off Tx 
F/U After
Prog  ƒ
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √
Continued Tx  √
REQUIRED STUDIES 
PRE 
W W W
W
W W
W
W W
W
W
W W W
W
W
W
W
W 
W
W 
 
STUDY
1
2
3
4
5
6
7
8
9
10
11 12 13 14 15
16
17 18
19 
20
21
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
X 
 
 
 
Xß
 
 
Xß
 
 
Xß
 
 
Xß 
 
 
Xß
 
 
Xß
 
 
X 
X 
Vital Signs 
Only  $ 
 
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X 
X 
X 
X 
X 
Weight and Performance Status 
X 
 
 
 
Xß
 
 
Xß
 
 
Xß
 
 
Xß 
 
 
Xß
 
 
Xß
 
 
X 
X 
Disease Assessment  ¶ 
X 
 
 
 
 
 
 
X
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Toxicity 
Notation  $ 
 
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X 
X 
X 
X 
X 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Differential/     Platelets  £ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
Serum Creatinine   ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
Calc or Meas CrCL  ¤ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
 
 
 
X 
X 
Total Bilirubin   § 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
SGOT or  
SGPT   § 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
Alkaline Phosphatase  ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albumin ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
LDH  ∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 
Serum Sodium , Calcium and 
Magnesium  †∞ 
X 
 
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
X 
 
 
X 
X 


 
 
S0819 
 
 
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Version Date 10/3/16 
 
 
 
 
 
NOTE:  All forms for this study can be found on the protocol abstract page of the SWOG website (www.swog.org).   Form Submission Guidelines can be 
found in Section 14.0. 
 
Click here for footnotes. 
9.4 (contd.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Off  Tx 
F/U Prior 
To Prog   ƒ
Off Tx 
F/U After
Prog  ƒ
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 √
Continued Tx  √
REQUIRED STUDIES 
PRE 
W W W W W W
W
W W
W
W
W
W W W
W
W
W
W 
W
W
 
STUDY
1
2
3
4
5
6
7
8
9
10 11 12
13 14 15 16 17 18
19 
20
21
 
 
SPECIMEN/ 
IMAGE SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Submission   * 
X 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Tissue 
Submission   * 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Image 
Submission   & 
X 
 
 
 
 
 
 
X
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT or MRI for disease assessment   ¶ 
X 
 
 
 
 
 
 
Xß
 
 
 
 
 
Xß 
 
 
 
 
 
Xß
 
 
X 
 
Brain CT/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan     Ω 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG     ¥ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT   ∆ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carboplatin 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
 
 
 
 
 
Paclitaxel 
 
X
 
 
X
 
 
X
 
 
X
 
 
X 
 
 
X
 
 
 
 
 
 
 
Cetuximab   √ 
 
X
X
X
X
X
X
X
X
X
X
X
X
X 
X 
X
X
X
X
X√
X 
X 
 
 


 
 
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Version Date 10/3/16 
 
 
 
 
Calendar 9.4 footnotes. 
 
 
 
 
 
 
∞  Results of these tests do not determine eligibility but are recommended prior to registration, during treatment and throughout follow-up in accordance with Good 
Medical Practice (see Section 7.1). 
†  In the event of hypomagnesemia, more frequent monitoring and magnesium repletion should be instituted as per routine clinical practice.
¶   CT or MRI (the same method used at prestudy to meet the eligibility criteria in Section 5.1c) must be repeated every 6 weeks until disease 
progression.  After 9 months from registration, the frequency of this scan may be reduced to every 3 months until disease progression.
 
¤   Calculated CrCL based on creatinine level obtained within 3 days prior to each dose is required to determine carboplatin dose. 
 
*    See Section 15.0. 
 
&  Submit scans to QARC as outlined in Sections 15.4 and Appendix 18.6. 
 
 
 
 
 
 
 
 
 
 
§   SGOT or SGPT and bilirubin is required within 7 days prior to each dose of paclitaxel/carboplatin. 
 
Ω   This test is required prestudy for Good Medical Practice only if clinically indicated.  It is recommended to be performed during treatment if clinically indicated. 
£   CBC should be obtained more frequently if patient is on G-CSF, per Section 8.6.
 
√   After completion of Cycle 6 and if the patient has not met criteria outlined in Section 7.8, cetuximab will be continued until one of the criteria in Section 7.8 is 
met. 
ƒ   After off treatment, patients should be followed by repeating indicated laboratory tests every 3 months for the first year, then every 6 months for up to 3 years 
from the date of registration. 
∆   See Sections 7.2 and 7.3.   
 
 
 
 
 
 
 
 
 
 
 
 
$   Patients will have vital signs taken (before, during and after treatment) and will be evaluated for toxicities at each visit during cetuximab treatment (see Section 
3.3c - "Administration of Cetuximab"). 
ß   To be performed within 7 days prior to starting cycle.
 
¥    This test is required prestudy for Good Medical Practice (see Section 7.1 for guidance on timing and interpretation of these test results). 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease:  Lesions that can be accurately measured in at least one 
dimension by 1) medical photograph (skin or oral lesion), palpation, plain x-ray, 
CT, MRI or other conventional technique with longest diameter 2 cm or greater in 
the axial plane (bone lesions not included), or 2) spiral CT with longest diameter 
1 cm or greater.  Ultrasound is suitable only for superficial disease (superficial 
palpable nodes, subcutaneous lesions, thyroid nodules). 
 
Conventional CT and MRI should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. 
 
b. 
Non-measurable disease:  All other lesions including lesions too small to be 
considered measurable, pleural or pericardial effusions, ascites, bone disease, 
inflammatory breast disease, leptomeningeal disease, lymphangitis, pulmonitis, 
abdominal masses not confirmed and followed by imaging techniques, cystic 
lesions or disease documented by indirect evidence only (e.g., by lab values), 
previously radiated lesions that have not progressed. 
 
10.2 
Objective Status 
 
Objective status at each evaluation:  Objective Status is to be recorded at each 
evaluation.  All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions 
in total, representative of all involved organs, should be identified as target lesions at 
baseline.  All measurable lesions not identified as target lesions are non-target lesions and 
are included as non-measurable disease.  Measurements must be provided for target 
measurable lesions, while presence or absence must be noted for non-target measurable 
and non-measurable disease. 
 
a. 
Complete Response (CR):  Complete disappearance of all measurable and 
non-measurable disease.  No new lesions.  No disease related symptoms.  
Normalization of markers and other abnormal lab values.  All disease must be 
assessed using the same technique as baseline. 
 
b. 
Partial Response (PR):  Applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline of the sum of 
longest diameters of all target measurable lesions.  No unequivocal progression of 
non-measurable disease.  No new lesions.  All target measurable lesions must be 
assessed using the same techniques as baseline. 
 
c. 
Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression:  One or more of the following must occur:  20% increase in the sum 
of longest diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline.  Unequivocal progression of non-measurable disease in the opinion of 
the treating physician (an explanation must be provided).  Appearance of any new 
lesion/site.  Death due to disease without prior documentation of progression and 
without symptomatic deterioration (see Section 10.2e). 
 
 


 
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e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown:  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
objective status except in determination of CR (must be absent--a patient 
who otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR), and in determination of progression (if new sites of disease 
develop or if unequivocal progression occurs in the opinion of the treating 
physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. 
 
6. 
Appearance or worsening of pleural effusions does not constitute 
unequivocal progression unless cytologically proven of neoplastic origin. 
 
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy or fine needle aspirate. 
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying 
as CR. 
 
 


 
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c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration:  Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above. 
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status   
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light 
housework, office work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair.   
 
10.5 
Progression-Free Survival (Central-Review Based) 
 
From date of randomization (which is the date of registration) to date of first 
documentation of progression based on Central Radiological Review of the appropriate 
CT or MRI scans, or symptomatic deterioration (as defined in Section 10.2.e), or 
development of new lesions or progression (as defined in Section 10.2d) documented by 
methods other than on CT or MRI, or death due to any cause.  Patients who have a local 
assessment of progression based on CT/MRI imaging, but for whom central review does 
not concur, will be censored at the last imaging date, unless documentation by 
subsequent reviewed CT/MRI scans, methods other than CR or MRI, or symptomatic 
deterioration provides evidence of progression.  Patients last known to be alive and 
progression-free are censored at the date of last contact. 


 
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10.6 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined in Sections 10.2d and 10.2e), or death due to any cause.  
Patients last known to be alive and progression-free are censored at date of last contact.  
 
10.7 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1   
Primary Endpoint 
 
Entire study population: The primary objective in the entire study population is to 
compare overall survival (OS) in advanced NSCLC patients treated with cetuximab 
chemotherapy plus bevacizumab (if appropriate) versus chemotherapy and bevacizumab 
(if appropriate). The addition of cetuximab will be judged to be superior if the true increase 
in median OS is 20%. 
 
EGFR FISH-positive cohort: The primary objective for this cohort is to compare 
progression-free survival (PFS) by institutional review in EGFR FISH-positive patients with 
advanced NSCLC treated with cetuximab-chemotherapy plus bevacizumab (if appropriate) 
versus chemotherapy and bevacizumab (if appropriate). The addition of cetuximab will be 
judged to be superior if the true increase in median PFS is 33%. 
 
11.2   
Secondary Endpoints 
 
Secondary objectives include the comparison of OS and PFS by centralized review in the 
EGFR FISH-positive cohort, PFS (by centralized review and institutional review) in the 
entire cohort, and response and toxicity in both study populations (entire cohort and EGFR 
FISH-positive cohort) treated with cetuximab and chemotherapy and bevacizumab (if 
appropriate) versus chemotherapy and bevacizumab (if appropriate), as well as to 
compare other purported EGFR-related biomarkers to EGFR IHC and EGFR FISH and to 
patient outcomes. K-ras mutational testing will be performed and correlated to response 
and outcome. Analysis for EGFR FISH and KRAS mutational status will be evaluated at 
each interim analysis. 
 
11.3  
H-Score 
 
Based on the FLEX trial, we assume that among patients with an IHC result, 26% will be 
determined to have a score > 200.  Assuming 95% of patients with an EGFR FISH result 
will have sufficient tissue for IHC, then 20% of patients will be classified as H-score 
positive (>200),  1174 patients will have an IHC result, and 306 patients will be available 
for the analysis of the efficacy of cetuximab (as measured by OS and PFS) among 
patients with an IHC >200. Further, based on the FLEX trial we assume that IHC score is 
not prognostic for either outcome.  It follows that this design has 82% power to detect a 
40% improvement in median PFS using a 1-sided 0.025 level stratified log-rank test.  This 
design also has 80% power to detect a 43% improvement in median OS using a 1-sided 
0.025 level stratified log-rank test.  If approximately 35% of patients positive for EGFR 
FISH also have an H-score > 200 (or equivalently 67% of H-score positive are EGFR 
FISH positive), then the expected numbers of patients in each biomarker category are as 
below: 


 
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No FISH result
EGFR FISH - 
EGFR FISH + 
Total 
No IHC result 
310 
31 
31 
372 (24%) 
IHC H-score < 200 
-- 
486 
382 
868 (56%) 
IHC H-score > 200 
-- 
101 
205 
306 (20%) 
Total 
310 (20%) 
618 (40%) 
618 (40%) 
1546 
 
11.4 
Sample Size With Power Justification 
 
This design employs co-primary objectives with OS within the entire study population and 
PFS by institutional review as the primary outcome in the EGFR FISH-positive group. 
Interim testing for efficacy is based on both PFS by institutional review and OS in the 
EGFR FISH-positive group. As the hypothesis within the EGFR FISH-positive group is 
partially nested (since PFS and OS are correlated) within the entire study hypothesis, (1-
sided) testing of the EGFR FISH-positive hypothesis at the 0.02 level and the entire study 
hypothesis at the 0.015 level results in an overall level of 0.025 (determined via 
simulation). 
 
Based on published and unpublished data (Fred Hirsch, personal communication), we 
expect at least 81% of patients will have adequate specimen for testing. The assay failure 
rate is estimated to be approximately 2% (98% success rate). Finally we assume that the 
proportion among those with a EGFR FISH assay result determined positive is 50%. 
Therefore, the assumed rate of EGFR FISH-positive patients among all patients enrolled 
is 40% (= 81% * 98% *50%). 
 
We assume for 50% of patients it will be inappropriate to receive bevacizumab, and that 
the median PFS in this group is less than that in the bevacizumab-appropriate group. The 
null median PFS is assumed to be 6 months for the bevacizumab-appropriate group, 
based on data from E4599. The null median PFS is assumed to be 4 months, for the 
bevacizumab-inappropriate group based on data from S0003. 
 
EGFR FISH-positive cohort: A design with 92% power, 4 years accrual, 1 year of follow-
up, requires 618 patients to detect a 33% improvement in median PFS, using a 0.02 1-
sided logrank test. This would require ~1,546 patients to be enrolled on study. 
 
Entire study population: Assuming 50% of patients are bevacizumab inappropriate, a 
median OS of 10 months in the bevacizumab-inappropriate stratum, and median OS of 12 
months in the bevacizumab-appropriate stratum this design has 86% power to detect a 
20% improvement in the entire cohort of 1,546 patients in median OS, using a 0.015 1-
sided level stratified logrank test. 
 
In summary: Entire study: 1,546 patients, EGFR FISH-positive: 618. 
 
11.5  
Analysis Plan Including Plans for Formal Interim Analysis 
 
Primary analyses will be performed on an intent-to-treat basis. A (stratified) log-rank test at 
the 0.02 level will be used to test the primary hypothesis in the EGFR FISH-positive cohort 
and at the 0.015 level in the entire study to achieve an overall type I error rate of 0.025. 
 
A formal interim analysis will be done after 30% of the expected progression events in the 
control arm (87 progression events) in the EGFR FISH-positive cohort, approximately 21 
months after the study opens, by which time about 266 EGFR FISH-positive patients and 
overall 665 patients will have entered into the study. Evidence suggesting early 
termination of the trial for superiority will only be formally assessed in the EGFR FISH  


 
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positive cohort and will be based on PFS and OS. Data on PFS and OS in the entire study 
population will be provided to the SWOG Data and Safety Monitoring Committee (DSMC). 
As such, in the EGFR FISH-positive cohort, the conclusion that the experimental arm is 
better than the control arm would be if the hypothesis of no difference in PFS were 
rejected at the one-sided 0.002 level and OS were rejected at the 0.004 level, or OS alone 
were rejected at 0.002 level. The level for OS is adjusted upward as the primary 
hypothesis within the FISH-positive cohort is PFS, but it is desired to establish a benefit in 
OS should the trial stop early for efficacy. The following table summarizes the conditions 
that are to be met for early stopping for superiority. 
 
Table 1 Conditions for stopping for superiority 
Reject null hypothesis: 
PFS 
 
OS 
EGFR FISH-positive cohort 
(P< 
0.002 
and 
P< 
0.004)
 
 
or 
P< 
0.002
Entire study cohort 
N/A 
 
N/A 
 
If the conditions in Table 1 are met then the recommendation will be to stop the EGFR 
FISH-positive group for efficacy. If at this time futility is not reached in the overall group 
and the EGFR FISH-positive group has been stopped, then the SWOG DSMC will 
consider all the evidence to determine if the study should continue in the EGFR FISH non-
positive group. 
 
Evidence suggesting early termination of the trial for futility will be formally assessed in the 
EGFR FISH-positive cohort and the entire study population. This assessment will be 
based on PFS in the EGFR FISH-positive cohort and based on PFS and OS in the entire 
study population For futility testing, the alternative hypothesis of at least 33% improvement 
in PFS for the experimental arm in the EGFR FISH-positive cohort will be tested at one-
sided level 0.002, using an extension of the logrank test that allows for testing a relative 
risk not equal to 1. Additionally, the alternative hypothesis of at least 20% improvement in 
PFS and OS for the experimental arm in the entire study population will be tested at one-
sided level 0.0015, also using the test that allows for testing a relative risk not equal to 1. 
Evidence suggesting early termination of the trial for futility will be that the alternative 
hypotheses are rejected for PFS in the EGFR FISH-positive cohort and PFS and OS in the 
entire study population. If the alternative hypotheses are rejected as specified above (PFS 
in EGFR FISH-positive, PFS and OS in the entire study), this will be considered evidence 
suggesting early termination of the trial for futility. The following table summarizing the 
conditions that are to be met for early stopping for futility. 
 
.


 
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Table 2 Conditions for stopping for futility 
Reject alternative hypothesis: 
PFS 
 
OS 
EGFR FISH-positive cohort 
P< 0.002
and 
N/A 
 
 
 
 
Entire study cohort 
(P< 
0.0015 
or 
P< 
0.0015) 
 
Evidence suggesting early termination of the study in the non-EGFR FISH positive cohort 
will be assessed in the entire study population and the non-positive cohort and will be 
based on PFS and OS. For futility testing, the alternative hypothesis of at least 20% 
improvement in PFS and OS for the experimental arm in the entire study population will be 
tested at one-sided level 0.0025, using a test that allows for testing a relative risk not 
equal to 1. Also, for futility testing, the alternative hypothesis of at least 10% improvement 
in PFS and OS for the experimental arm in the EGFR FISH non-positive will be tested at 
one-sided level 0.0025, using a test that allows for testing a relative risk not equal to 1. 
Evidence suggesting early termination of the trial for futility will be that the alternative 
hypothesis is rejected for either PFS or OS in the EGFR FISH-positive cohort or the entire 
study population. 
 
Table 3 Conditions for stopping EGFR FISH non-positive cohort for futility 
Reject alternative hypothesis: 
PFS 
 
OS 
EGFR FISH non-positive cohort
P< 
0.0025
or 
P < 
0.0025
 
 
 
 
Entire study cohort 
P< 
0.025 
or 
P < 
0.0025
 
The actual decision to terminate accrual early will be made by the DSMC, and will 
consider K-ras mutations, response, toxicities and other factors in addition to PFS and OS. 
 
A second interim analysis is planned when 2/3 of the expected events in the control arm 
have occurred, which will be at approximately 39 months after the study opens, with 
roughly 199 events and an expected 500 accrued in the EGFR FISH-positive cohort and 
1,250 overall. Testing of the null and alternative hypotheses will proceed as described for 
the first interim analysis. A third interim analysis is planned when 85% of the expected 
events in the control arm have occurred, which will be approximately 48 months after the 
study opens, with roughly 252 events and accrual to the study completed. Testing of the 
null and the alternative hypotheses will proceed as described for the first interim analysis. 
Should a study cohort be stopped at a previous interim analysis, the recommendation will 
be based on the rules associated with the current study population. If the decision is to 
continue the study, the final analysis will take place when at least 297 events in EGFR 
FISH-positive cohort have occurred, approximately 60 months after the study opens. The 
final analysis in the EGFR FISH-positive cohort will be at level 0.014 (one-sided test) to 
allow for the effects of interim testing. A modified Haybittle-Peto approach is used to 
determine alpha spending. The following table summarizes the expected number 
 


 
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Table 4 Description of planned interim and final analyses based on events in control arm 
 
 
 
 
 
 
 
 
 
 
In addition to the EGFR FISH assay, K-ras will be assessed on the patient specimens for 
each interim analysis and as a planned subgroup analysis upon study completion. 
Planned analyses to assess the safety of cetuximab in patients with K-ras mutations are a 
comparison of OS and PFS by treatment arm using a stratified log-rank test. Analyses 
following the specifications for the entire study cohort will also be performed within the 
bevacizumab and non-bevacizumab treated patients to assess safety and efficacy/futility 
at each interim analysis and as a planned subgroup analysis upon study completion. 
These analyses will be provided to the SWOG DSMC. 
 
At each analysis, the design assumptions regarding proportions of EGFR FISH-positive 
patients, numbers of adequate specimens, and assay performance will be evaluated. The 
number of enrolled patients may be adjusted if the proportion of enrolled patients 
determined to be EGFR FISH-positive is different than expected to accrue 618 EGFR 
FISH-positive patients. 
 
Secondary analyses will also be done regarding OS in the EGFR FISH-positive cohort and 
PFS in the entire study (using a stratified log-rank test), and response and toxicity (using 
stratified chi-square tests). This design has 87% power to detect a 33% improvement in 
OS in the EGFR FISH-positive group using a 1-sided 0.02 level log-rank test. Additionally, 
this design has 91% power to detect a 20% improvement in PFS in the entire study 
population using a 1-sided 0.015 level log-rank test. With 309 patients per arm in the 
EGFR FISH-positive group, response and toxicity rates can be estimated to within at worst 
± 6% (95% confidence interval). With 773 patients per arm in the entire study, response 
and toxicity rates can be estimated to within at worst ± 4% (95% confidence interval). 
 
The predictive effect of EGFR FISH will be assessed by testing an interaction between 
EGFR FISH status and treatment in the respective regression model among the 1,236 
patients with a FISH result (80% of 1,546). Assuming EGFR FISH is not prognostic, this 
design has 58% power to detect a difference in hazard ratios for PFS (1.1 versus 1.33) 
using a 1-sided 0.05 level log-rank test. Analyses will also be performed within the 
stratification factor grouping to assess treatment effects within each group. Supportive 
analyses of the effect of baseline characteristics on survival and progression free survival 
will be performed using Cox proportional hazards regression modeling. Similarly, the effect 
of baseline characteristics on response rate will be explored with logistic regression 
analysis. In addition to the stratification factors, other clinical covariates will include (but 
may not be limited to) age, gender, race and prior weight loss. 
 
11.6  
Amendment to design 
 
S0819 was placed in temporary closure to further accrual on June 1, 2014. As of this date, 
400 eligible EGFR FISH positive patients had been accrued to the study.  Following 
review of the pre-specified second interim analysis, further accrual to the EGFR FISH non-
positive cohort was terminated upon the recommendation of the DSMC.  Prior to this 
analysis and independent of the study data, the study team had planned to modify the 
Time 
EGFR FISH-positive
Overall Population
Percent of: 
(mo) 
# Prog 
# Deaths 
# Prog 
# Deaths 
Prog 
Deaths Accrual 
21 
89 
59 
223 
148 
30% 
23% 
43% 
39 
199 
153 
498 
383 
67% 
59% 
81% 
48 
252 
207 
630 
518 
85% 
80% 
100% 
60 
297 
259 
743 
648 
100% 
100% 
100% 


 
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study design with the EGFR FISH positive cohort due to a lower than anticipated 
percentage of patients defined to be EGFR FISH positive and lower than anticipated total 
accrual rate.  The study design within the EGFR FISH positive cohort has been modified 
to a design with 80% power to detect a 33% improvement in median PFS.  As result of the 
closure of the EGFR FISH non-positive cohort, the hypothesis within the overall population 
will not be tested and no type I error will be spent on that hypothesis. An additional 
specification is to change the overall type I error to 0.025 from 0.02 in the EGFR FISH 
positive cohort. The final level of testing will be performed at the 0.021 to account for the 
effects of interim testing (a change from 0.014).  Testing will still be performed using a 1-
sided log-rank test. Given the modified design assumptions, 386 progression events are 
needed to detect a 33% improvement in median PFS with 80% power at the 1-sided 0.025 
level.  Due to logistical considerations, the study team determined it would be preferable to 
extend follow-up among the EGFR FISH positive patients instead of re-opening the study 
to further accrual in this population.  The third interim analysis at 85% information has 
been dropped, as well.  In order to achieve 386 events, the follow-up duration has been 
extended from 1 year to 2 years.  The final analysis will occur upon the observation of 386 
progression events in the EGFR FISH positive cohort or by June 2016, whichever comes 
first. All other analyses will proceed as previously specified.  The following table 
summarizes the changes to the design. 
 
 
Original Design 
Modified Design 
Alternative hypothesis (HR) 
1.33 
Same 
Power 
92% 
80% 
Overall Type I error 
0.02 
0.025 
Number of interim analyses 
3 
2 
Final level of testing 
0.014 
0.021 
Follow-up duration 
12 months 
24 months 
PFS events at analysis 
588 
386 
Sample Size (eligible) 
618 
400 
 
11.7 
Accrual Information 
 
Accrual Rate: 35-40 pts/month. S0003 accrued approximately 240 patients/year and 
SWOG-9509 accrued approximately 300 patients per year in SWOG alone. This study will 
be available on the CTSU menu. With intergroup participation we anticipate accrual of 
approximately 400 patients per year. 


 
 
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11.8 
Data and Safety Monitoring Committee 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study. The 
Committee consists of four members from outside of SWOG. Group members, 3 non-
voting representatives from the National Cancer Institute (NCI), and the Group Statistician 
(non-voting). The members of this Committee will receive confidential reports every 6 
months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary. The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
This section does not apply to this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1  
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than seven working 
days prior to planned start of treatment). 
 
13.2 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 
g. 
Patient Initials 
 
h. 
Patient’s Date of Birth 
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 


 
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k. 
ZIP Code 
 
l. 
Gender (select one): 
 
Female Gender 
 
Male Gender 
 
m. 
Ethnicity (select one): 
 
Hispanic or Latino 
 
Not Hispanic or Latino 
 
Unknown 
 
n. 
Method of Payment (select one): 
 
Private Insurance 
 
Medicare 
 
Medicare and Private Insurance 
 
Medicaid 
 
Medicaid and Medicare 
 
Military or Veterans Sponsored NOS 
 
Military Sponsored (Including Champus & Tricare) 
 
Veterans Sponsored 
 
Self Pay (No Insurance) 
 
No Means of Payment (No Insurance) 
 
Other 
 
Unknown 
 
o. 
Race (select all that apply): 
 
American Indian or Alaska Native 
 
Asian 
 
Black or African American 
 
Native Hawaiian or other Pacific Islander 
 
White 
 
Unknown 
 
13.3 
Registration Procedures 
 
a. 
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this 
study.  OPEN is a web-based application and can be accessed from the CTSU 
members' web site OPEN tab, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench.  
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
 
All eligibility criteria have been met within the protocol stated 
timeframes. Site staff should refer to Section 5.0 to verify eligibility. 
 
 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
  
c. 
Access requirements for OPEN: 
  
 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user ID and password) 
used for the CTSU members' web site.  
 
 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the SWOG or CTSU roster:  


 
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1. If you are a SWOG member, to perform registrations on SWOG 
protocols you must have an equivalent 'Registrar' role on the SWOG 
roster.  Role assignments are handled through SWOG.  
 
2. If you are not a SWOG member, to perform registrations on SWOG 
protocols you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via 
the new Site Roles maintenance feature under RSS on the CTSU 
members' web site. This will allow them to assign staff the "Registrar" 
role.  
 
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records.   
 
d. 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.4  
Registration Exceptions  
 
For either method of registration, exceptions to SWOG registration policies will not be 
permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
14.2 
Master Forms  
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Form) must be submitted to the Data Operations Center in Seattle.  Data from approved 
SWOG institutions must be submitted on-line via the Web; see Section 14.3a for details.  
Exceptions to online data submission are patient-completed (e.g. Quality of Life) forms 
and source documents (e.g. pathology/operative/lab reports). 
 


 
 
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14.3 
Data Submission Procedures   
 
a. 
SWOG institutions must submit data electronically via the Web by using the 
SWOG CRA Workbench.  To access the CRA Workbench, go to the SWOG Web 
site (http://swog.org) and logon to the Members Area.   After you have logged on, 
click on the CRA Workbench link to access the home page for CRA Workbench 
website.  Next, click on the Data Submission link and follow the instructions.  For 
new users, the link to a "Starter Kit" of help files may be found by clicking on the 
Starter Kit link at the Members’ logon page. 
 
To submit data via the web the following must be done (in order): 
 
1.  
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2.  
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3.  
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do not 
use cover sheet for faxed data. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS OF REGISTRATION: 
 
Submit a copy of the following: 
 
S0819 Prestudy Form 
 
Baseline Tumor Assessment Form 
 
Pathology Report 
 
SWOG S0819 Pathology Review Form (Appendix 18.8) 
 
Radiology reports from all scans performed to assess disease at baseline 
 
Operative reports from all surgical or biopsy procedures performed within 28 days 
prior to registration. 
 
b. 
WITHIN 14 DAYS AFTER REGISTRATION: 
 
Submit prestudy specimens as outlined in Section 15.1a 
 
Submit images for central review as outlined in Appendix 18.6. 
 


 
 
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c. 
WITHIN 7 DAYS AFTER EACH CYCLE (1 CYCLE = 21 DAYS) OF TREATMENT: 
 
Submit a copy of the following: 
 
S0819 Treatment Form  
 
S0819 Adverse Event Form. 
 
d. 
AT WEEK 7: 
 
Submit blood specimens as outlined in Section 15.1a. 
 
e. 
AFTER EVERY TUMOR ASSESSMENT UNTIL DISEASE PROGRESSION (see 
Section 9.0 for Disease Assessment Schedule): 
 
Submit a copy of the following: 
 
Follow-Up Tumor Assessment Form   
 
Radiology reports from all scans performed to assess disease  
 
Submit images for central review as outlined in Appendix 18.6. 
 
f. 
WITHIN 14 DAYS OF PROGRESSION OR RELAPSE: 
 
Submit a copy of the following: 
 
Lung Carcinoma First Site(s) of Progression or Relapse Form 
 
Follow-Up Tumor Assessment Form 
 
If the patient is off protocol treatment, submit the Advanced NSCLC Follow Up 
Form 
 
Submit images for central review as outlined in Appendix 18.6. 
 
g. 
WITHIN 14 DAYS OF DISCONTINUATION OF ALL PROTOCOL TREATMENT: 
 
Submit a copy of the following: 
 
Off Treatment Notice documenting the date of completion of protocol treatment, 
progression/relapse/other reason, and summarizing inclusive dates of treatment 
and patient status 
 
Final S0819 Treatment Form   
 
Final S0819 Adverse Event Form  
 
Submit plasma and buffy coat as outlined in Section 15.1a. 
 
h. 
WITHIN 14 DAYS AFTER DIAGNOSIS OF SECOND MALIGNANCY:   
 
Submit the Advanced NSCLC Follow Up Form. 
 


 
 
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i. 
ONCE OFF ALL PROTOCOL TREATMENT, SUBMIT EVERY 6 MONTHS FOR 
UP TO 3 YEARS FROM THE DATE OF REGISTRATION: 
 
Submit the Advanced NSCLC Follow Up Form. 
 
j. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit a copy of the Notice of Death.  If the patient was off protocol treatment at 
the time of death, submit a Advanced NSCLC Follow Up Form. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Required Tissue Specimens for EGFR FISH and KRAS 
 
Specimens for EGFR FISH and KRAS mutation analysis (submitted to the University of 
Colorado) (Required): 
 
a.  
Specimens must be submitted at the timepoints listed below.  Collection 
instructions are outlined in Section 15.1c and submission instructions are outlined 
in Section 15.1e. 
 
b. 
Specimens must be submitted at the following times (see Section(s) 9.1 – 9.4): 
 
1. 
Paraffin-embedded tissue/Prestudy 
 
c. 
Specimen Collection Instructions 
 
 
Submit 1-2 paraffin-embedded tissue blocks containing formalin fixed tumor or 
needle aspirate slides from time of diagnosis (or subsequent, but prior to therapy) 
must be submitted for evaluation of expression of relevant molecular targets. 
Paraffin blocks may be processed according to standard institutional protocols. If 
blocks are unavailable, 10-12 unstained slides are acceptable alternatives. 
Cytology (i.e. fine-needle aspirations) can be accepted only if they are paraffin 
embedded as cell blocks. Tumor material must be reviewed by a local pathologist 
to ensure sufficient tumor cells are present in the sample. The local pathologist 
must review and sign off on the SWOG S0819 Pathology Review Form 
(Appendix 18.8) noting that there are at least 100 tumor cells present in the 
sample. The number of cells present in the sample must be entered into the 
Specimen Tracking System along with copies of the SWOG S0819 Pathology 
Review Form and the pathology report when the specimen is submitted to the 
SWOG Solid Tumor Repository. Please also fax the SWOG S0819 Pathology 
Review Form to the Data Operations Center at 800/892-4007 or 206/342-1680 
locally. These samples must be submitted for expression of relevant integral 
molecular targets (see Section 15.3). 
 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 


 
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e. 
Shipping Samples 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked 
using the SWOG online Specimen Tracking system. SWOG members 
may log on the online system via the CRA Workbench. To access the 
CRA Workbench, go to the SWOG Web site (http://swog.org) and logon to 
the Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. First time non- SWOG users 
must refer to start-up instructions located at 
https://gill:crab.org/SpecTrack/. 
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The 
Specimen Submission Form is NOT required when the online system is 
used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact 
the Data Operations Center at 206/667-2267 to be routed to the Data 
Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of paraffin-embedded tissue for EGFR FISH and KRAS 
mutation analysis is identified as follows: 
 
Lab #78:  
UCD Biorepository Core Facility 
Department of Pathology 
RC-1 North, Room P18-5404M 
12801 East 17th Avenue 
Aurora, CO 80045 
 
Contact:  
Adrie van Bokhoven 
Phone: 303/724-3908 
E-mail: Adrie.vanBokhoven@ucdenver.edu 
 
f. 
The Federal guidelines for shipment are as follows: 
 
1.  
The specimen must be wrapped in an absorbable material; 
 
2.  
The specimen must then be placed in an AIRTIGHT container resealable 
bag); 
 
3.  
Pack the resealable bag and specimen in a Styrofoam container; 
 


 
 
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4. 
Pack the styrofoam shipping container in a cardboard box. 
 
5.  
The cardboard box must be marked as "BIOHAZARD." 
 
15.2 
Required Plasma and Buffy Coat for Translational Medicine and Optional Banking 
 
Specimens for correlative studies and banking (submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201) (Required): 
 
a.  
Specimens must be collected at the following times and submitted (see Section(s) 
9.1 - 9.4): 
 
1.  
Draw 10 ml of plasma and buffy coat specimens into two 5 – 10 cc purple 
top (EDTA) tubes at the following timepoints: 
 
a.  
Prior to treatment (prestudy) 
 
b. 
Week 7 
 
c.  
At time of removal from protocol treatment. It is important that a 
blood specimen also be obtained from any patient when he/she 
is removed from protocol treatment or has disease progression. 
Blood should be processed as soon as possible after 
venipuncture, preferably within two hours. Samples not 
processed immediately after blood draw should be refrigerated 
at 4°C until processing. The tubes will be immediately 
centrifuged at approximately 1,200 rpm for 10 minutes. Buffy 
coat cells will be removed and placed in labeled cryotubes. 
Plasma will be separately removed and placed in 4 (2 mL) 
labeled cryotubes. All tubes are then to be frozen. Store frozen 
at -80°C until shipped to the SWOG Specimen Repository on 
dry ice as detailed on the specimen submission webpage (see 
Section 15.2b). These samples must be submitted for 
expression of relevant integral molecular targets (see Section 
15.3). 
 
b.  
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via the 
link on the S0819 protocol abstract page on the SWOG website (www.swog.org). 
 
c. 
Specimen collection kits may be ordered by calling the SWOG Specimen 
Repository at 614/722-2865. 
 
15.3 
Integral Translational Medicine Studies 
 
The study includes embedded integral translational medicine studies (e.g., tests that must 
be performed in order to conduct the trial): EGFR FISH and KRAS mutation analysis. 
Thus, both tissue (EGFR FISH) and blood specimens (KRAS mutations) are mandatory 
for this study in order to perform the integral correlative studies. 
 
EGFR FISH:  Among enrolled patients, EGFR FISH will be performed on paraffin 
embedded material and by using the classification system developed by SWOG 
investigators, in which the results of the EGFR gene copy number will be reported as 
either EGFR FISH-positive, which includes patients with a tumor having high polysomy 
(>/= 4 copies of the gene in >/= 40% of the cells) or gene amplification  


 
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(gene/chromosome ratio > 2, or presence of gene clusters or >/= 15 gene copies in > 10% 
of the cells) or EGFR FISH-negative, which includes all other patients. This classification 
has been validated in several previous SWOG studies as well as in several prospective 
clinical trials. (8-11, 25)  
 
The EGFR FISH analysis in this study will be performed in the Dept of Pathology, 
University of Colorado under the direction of Dr. Marileila Varella-Garcia (CLIA certified 
laboratorium). 
 
KRAS mutation analysis:  Retrospective studies, including those by SWOG lung 
investigators, have found an association between KRAS mutation (codon 12/13) and 
resistance to EGFR TKIs. Few KRAS data are available for cetuximab in NSCLC, but an 
association with resistance has been demonstrated in colorectal cancer.  KRAS mutations 
occur in about 30% of lung adenocarcinomas and in 10-15% of non-adenocarcinomas, all 
together in about 20% of unselected NSCLC patients. We intend to analyze tumor tissue 
and plasma for KRAS mutation analysis in all patients treated on the S0819 clinical trial in 
real time and to incorporate this information into interim analyses, and well as to correlate 
results with outcomes and with the results of other biomarkers.  The KRAS mutation 
analysis will be performed at UC Davis by Dr. Philip Mack using the DxS Scorpion method 
as the principle method of analysis and automated SSCP augmented by cold PCR as 
additional validation.  For patients where tissue is not available, or is insufficient for 
analysis, we will analyze DNA extracted from plasma. These methods are described in the 
following paragraph. 
 
Allele-specific real-time PCR using scorpion primer and the Amplification Refractory 
Mutations System (Scorpions-ARMS) will be used to detect the presence of KRAS 
mutations.  (26-32)  Scorpion primers (produced by DxS LTD, Manchester, UK) are 
multifunctional molecules composed of a PCR primer, a fluorophore and a quencher (see 
Figure 1).  In the presence of its target sequence (in this case, a WT or mutant KRAS 
amplicon with a codon 12 or 13 base substitution), the scorpion primer undergoes an 
internal conformation rearrangement that releases the fluorophore from the quencher, 
resulting in a detectable light output. Scorpion-ARMS primers recognize the following 
KRAS point mutations: for codon 12, GGTGCT (GlyAla), GGTGAT (GlyAsp), 
GGTCGT (GlyArg), GGTTGT (GlyCys), GGTAGT (GlySer), GGTGTT 
(GlyVal), for codon 13, GGCGAC (GlyAsp).  Sensitivity for Scorpions-ARMS, 
depending upon the quality/quantity of the available source material (tissue or plasma) 
approaches 1% mutation detection in a wild-type background.  A secondary method, 
single-stranded conformation polymorphism (SSCP) using cold-PCR for mutation 
enrichment will be used for validation.  Cold PCR is a recently described method for 
mutation enrichment exploiting differential melting temperatures in heterozygous. (33,34)  
Specimens are run on a GenePhor electrophoresis (GE) unit with automated silver 
staining.  We have established primers and conditions that are sufficient to detect (at a 
threshold of 2-5%) all mutations obtained by Scorpion-ARMS as well as the following 
additional mutations; for codon 12, GGTTTT (GlyPhe), and for codon 13 GGCTGC 
(GlyAsp), with each base substitution resulting in a unique gel migration pattern (see 
Figure 2).  We have also detected additional rare double base-pair mutations, as well as 
alterations outside of codon 12 and 13 using this technique.  


 
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Figure 1. Scorpion-ARMS Strategy 
 
Target Template
Target Template
Figure 2. KRAS Mutation Detection 
using cold PCR and SSCP.  
Cell line controls. 
 
 
A549
Calu-1
H1650
H727
SW480
H1975
H358
H23A
H460
A427
H1355
SW116
AGT
TGT
GCT
TGC*
GAT
GTT
GGT
A549
Calu-1
H1650
H727
SW480
H1975
H358
H23A
H460
A427
H1355
SW116
AGT
TGT
GCT
TGC*
GAT
GTT
GGT
 
*codon 13 


 
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Definition of KRAS positivity: The cycle threshold (CT) is defined as the fractional cycle 
number at which the fluorescence passes the fixed threshold, set above baseline, as 
determined by the software.  For each probe set specific to a KRAS codon 12 or 13 base 
substitution, a cut-off deltaCT, defined as the CT of the mutant minus the CT of the wild 
type control, has been established by the manufacturer as the point at which a positive 
signal could be due to background fluorescence of the primer on wild-type DNA.  For our 
purposes, any specimen where the control probe has a CT value of >/= 40 will be 
repeated and/or disqualified as insufficient material.  For a patient specimen to be 
considered positive for mutation it must have: 1) a mutation CT < 45, 2) a deltaCT lower 
than the cut-off for that probe and 3) a smooth amplification curve in the log phase parallel 
to the control probe.  In addition, an independent validation assay will be conducted for 
each specimen using SSCP.  Due to formalin-induced DNA artifacts in archival tumor 
specimens, mutant positivity will likely be skewed slightly at the lower threshold.  (32)  As 
such, all tissue specimens will be compared, based upon sample size and quality of DNA, 
to determine the appropriate threshold below which any positivity will be determined to 
result from background artifacts.  In addition, differentially migrating bands in the SSCP 
gel can be isolated, extracted and sequenced to confirm mutations.  Divergent results 
between the DxS Scorpion-ARMS method and SSCP will result in re-analysis from, if at all 
possible, an additional tumor specimen and repeat of assays. Microdissection and 
sequencing can be used to resolve any further discrepancies, if required.  Plasma analysis 
is expected to generate cleaner results due to lack of formalin-induced artifact formation, 
however the quantity of total DNA and mutant DNA extracted may vary tremendously on a 
patient-to-patient basis.  (29, 30)  Therefore, while plasma DNA may confirm the presence 
of a mutation in a tissue specimen, any discrepancy between tissue and plasma will be 
resolved in favor of the tissue results.  Results from plasma analysis will be used as a 
back-up for patients where tumor tissue is insufficient or not available.  If the mutation 
status remains ambiguous after the rigorous testing outlined above has been completed 
and no additional specimens are available for analysis, the KRAS status for that patient 
will be considered undeterminable.  Our experience is that this will occur in less than 3% 
of cases. 
 
In order to compare the results of the FISH assay with other EGFR-related markers, other 
markers also be assessed in specimens from this trial as integrated translational medicine 
studies (e.g., tests that are clearly identified as part of the clinical trial from the beginning 
and intended to identify or validate assays or markers planned for future studies, see 
Section 18.5). 
 
15.4  
Radiology Review 
 
PET/CT, CT and MRI images will be initially interpreted by the local site radiologist.  
Imaging exams will then be forwarded to the Quality Assurance Review Center (QARC) 
for central review. 
 
All CT and/or MRI images must be submitted to QARC for central review.   
 
All study participants will have a PET/CT, CT or MRI exam prior to study entry.  
Participants will then undergo additional imaging every 6 weeks until progression of 
disease.  The same imaging modality used for the pre-treatment exam must be used for 
the post-treatment exams (i.e., patients with a pre-study PET/CT are to receive follow-up 
PET/CT scans throughout the trial for assessment of progression; patients with a pre-
study CT are to receive follow-up CT scans throughout the trial for assessment of 
progression; patients with a pre-study MRI are to receive follow-up MRI scans throughout 
the trial for assessment of progression).  Each exam should be performed per Appendix 
18.6.  QARC will facilitate a central/expert review per RECIST criteria; the central review- 


 
 
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based PFS is the basis for the assessment of objectives (see Section1.2a and 1.2b.  
Clinical management and treatment decisions will be made by the treating physician 
based on local site assessments and other clinically appropriate considerations.  Results 
of the central review will be reported only to the DSMC.  A detailed description of the 
central radiology PFS review, including image acquisition parameters and image 
submission instructions, can be found in Appendix 18.6. 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
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 using similar agents. Adverse events 
are reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse 
events must be reported in an expedited manner to allow for more timely 
monitoring of patient safety and care. The following guidelines prescribe expedited 
adverse event reporting for this protocol. See also Appendix 18.1 for general and 
background information about expedited reporting. 
 
b. 
Reporting methods 
 
This study requires that expedited adverse event reporting use the NCI’s Adverse 
Event Reporting System (CTEP-AERS).  The NCI’s guidelines for CTEP-AERS 
can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even
ts.htm. 
 


 
 
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In the rare event when internet connectivity is disrupted an electronic report MUST 
be submitted immediately upon re-establishment of internet connection.  Please 
note that all paper CTEP-AERS forms have been removed from the CTEP 
website and will NO LONGER be accepted. 
 
c. 
When to report an event in an expedited manner 
 
When the adverse event requires expedited reporting, submit the report within 10 
calendar days of learning of the event. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must also be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.1. If there is any 
question about the reportability of an adverse event or if on-line CTEP-AERS 
cannot be used, please telephone or email the SAE Program at the Operations 
Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
Table 
16.1. 
Expedited 
reporting 
requirements 
for 
adverse 
events 
experienced by patients who have received commercial drugs on this study. 
All of the agents used in this study are commercial agents. 
 
 
Attribution 
 
Grade 4 
 
Grade 5 a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated or 
Unlikely 
 
 
CTEP-AERS CTEP-AERS 
Possible, Probable, 
Definite 
CTEP-AERS
 
CTEP-AERS CTEP-AERS 
CTEP-AERS: 
 Indicates an expedited report is to be submitted via NCI CTEP-
AERS within 10 calendar days of learning of the eventb. 
 
a This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent(s), regardless of attribution. Any death that occurs more than 30 
days after the last dose of treatment with a commercial agent(s) and is attributed 
(possibly, probably, or definitely) to the agent(s) and is not due to cancer 
recurrence must be reported according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments 
generally completes the reporting requirements. You may, however, be asked to 
submit supporting clinical data to the Operations Office in order to complete the 
evaluation of the event. If requested, the specified data should be sent by fax to 
210-614-0006. 
 
 
 


 
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17.0 
BIBLIOGRAPHY 
 
1. 
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada 
Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 
353:123-32, 2005.  
 
2. 
Tsao M-S, Sakurada A, Cutz J-C: Erlotinib in lung cancer- molecular and clinical predictors of 
outcome. N Engl J Med 353: 133-144. 2005. 
 
3. 
Zhu C-Q, da Cunha Santos G, Ding K et al: Role of KRAS and EGFR as biomarkers of 
response to erlotinib in national Cancer Institute of Canada Clinical Trials Group study BR-21. 
J Clin Oncol 26 (E pub, July 14. 2008):  
 
4. 
Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Molecular predictors of outcome with 
gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin 
Oncol 24:5034-5042, 2006. 
 
5. 
Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor 
and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung 
cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 
23:5900-5909, 2005. 
 
6. 
Mukohara T, Engelman  J, Hanna N et al. Differential effects of gefitinib and cetuximab on 
non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl 
Cancer Inst. 97:1185-94, 2005.  
 
7. 
Meert AP, Martin B, Delmotte P, et al. The role of EGF-R expression on patient survival in 
lung cancer: a systematic review with meta-analysis. Eur Respir J 20:975-981, 2002. 
 
8. 
Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor 
gene copy number detected by fluorescence in situ hybridization associates with increased 
sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest 
Oncology Group Study. J Clin Oncol 23:6838-6845, 2005. 
 
9. 
Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in non-
small-cell lung carcinomas: correlation between gene copy number and protein expression 
and impact on prognosis. J Clin Oncol 21:3798-3807, 2003. 
 
10. 
Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein 
and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005.  
 
11. 
Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by FISH 
predicts outcome in non-small cell lung cancer patients treated with cetuximab and 
chemotherapy. J Clin Oncol 26: 3351-3357, 2008.  
 
12. 
Jeon YK, Sung SW, Chung JH, Park WS, Seo JW, Kim CW, Chung DH. Clinicopathologic 
features and prognostic implications of epidermal growth factor receptor (EGFR) gene copy 
number and protein expression in non-small cell lung cancer. Lung Cancer 54:387-98, 2006.  
 
13. 
Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, Jarrett C, Carter J, 
Murphy BA, Netterville J, Burkey BB, Sinard R, Cmelak A, Levy S, Yarbrough WG, Slebos 
RJ, Hirsch FR. Increased epidermal growth factor receptor gene copy number is associated 
with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 24:4170-6, 
2006. 


 
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14. 
Dziadziuszko R, Holm B, Skov BG, Osterlind K, Sellers MV, Franklin WA, Bunn PA Jr, 
Varella-Garcia M, Hirsch FR. Epidermal growth factor receptor gene copy number and 
protein level are not associated with outcome of non-small-cell lung cancer patients treated 
with chemotherapy. Ann Oncol 18:447-52, 2007. 
 
15. 
Douillard JY, Kim E, Hirsch V, et al. Gefitinib (IRESSA) versus docetaxel in patients with 
locally advanced or metastatic non-small-cell lung cancer pre-treated with platinum-based 
chemotherapy: a randomized, open-label phase III study (INTEREST). J Thorac Oncol 2: 
S305, 2007.  
 
16. 
Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O, 
Stroh C, Rougier P. KRAS status and efficacy in the first-line treatment of patients with 
metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The 
CRYSTAL experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 2)  
 
17. 
Gandara DR, Gumerlock PH. Epidermal growth factor receptor tyrosine kinase inhibitors plus 
chemotherapy: case closed or is the jury still out? J Clin Oncol. 23:5856-8, 2005.  
 
18. 
Lynch TJ, Patel T, Dreisbach L, et al. A randomized multicenter phase III study of cetuximab 
(Erbitux) in combination with Taxane/Carboplatin versus Taxane/Carboplatin alone as first-
line treatment for patients with advanced/metastatic Non-small cell lung cancer (NSCLC).  
IASLC 12th World Conference on Lung Cancer, 2007. 
 
19. 
Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of 
cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line 
treatment of patients with advanced non-small cell lung cancer. J Clin Oncol 26: 1006s, 2008. 
 
20. 
Taguchi F, Solomon B, Grecorg V, et al. Mass spectrometry to classify non-small cell lung 
cancer patients for clinical outcome after treatment with epidermal growth factor receptor 
tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 99: 838-
846, 2007.  
 
21. 
Eberhard DA, Giaccone G, Johnson BE.  Biomarkers of response to epidermal growth factor 
receptor inhibitors in non-small-cell lung cancer working group:  standardization for use in the 
clinical trials setting.  J Clin Oncol 26:  983-994, 2008. 
 
22. 
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors 
in controlled clinical trials.  Biometrics 31:103-115, 1975. 
 
23. 
Tsao MS, Aviel-Ronen S, Ding K, et al.  Prognostic and predictive importance of p53 and 
RAS for adjuvant chemotherapy in non-small cell lung cancer.  J Clin Oncol 25(33):5240-47, 
2007. 
 
24. 
Punt CJ, Tol J, Rodenburg CJ, et al.  Randomized phase III study of capecitabine, oxaliplatin 
and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the 
CAIRO2 study of the Dutch colorectal cancer group (DCCG).  J Clin Oncol 26 (May 20 suppl; 
abstr LBA4011), 2008. 
 
25. 
Hirsch FR, Varella-Garcia M, Bunn PA, et al,  Fluorescence in situ hybridization (FISH) 
subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in 
NSCLC.  J Clin Oncol 25(18S) (June 20 suppl:abstr 7570), 2007. 
 
26. 
Whitcombe D, Theaker J, Guy SP, et al. Detection of PCR products using self-probing 
amplicons and fluorescence. Nature Biotech 17:804-807, 1999. 
 


 
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Version Date 10/3/16 
 
 
 
 
27. 
Thelwell N, Millington S, Solinas A, et al. Mode of action and application of scorpion primers 
to mutation detection. Nucleic Acids Research 28(19):3752-3761, 2000. 
 
28. 
Clayton SJ, Scott F, Walker J, et al. K-ras point detection mutation in lung cancer. Clinical 
Chemistry 46(12):1929-1938, 2000 
 
29. 
Kuang Y, Rogers A, Yeap BY, et al. Noninvasive detection of EGFR T790M in gefitinib or 
erlotinib resistant non-small cell lung cancer. Clin Cancer Res 15:2630-6, 2009 
 
30. 
Mack PC, Holland WS, Burich RA, et al. Predictive value of EGFR and KRAS mutations 
detected in plasma from non-small cell lung cancer (NSCLC) patients treated with docetaxel 
and intermittent erlotinib. JCO Vol 26, No 15S (May 20 Supplement): 8062, 2008. 
 
31. 
Amado RG, Wolf M, Peeters M, et al.  Wild-type KRAS is required for panitumumab efficacy 
in patients with metastatic colorectal cancer. JCO Vol 26:1626-1634, 2008. 
 
32. 
Jimeno A, Messersmith WA, Hirsch FR, et al. KRAS mutations and sensitivity to epidermal 
growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. 
JCO Vol 27, No 7: pp. 1130-1136, 2009. 
 
33. 
Li J, Wang L, Mamon H, et al. Replacing PCR with COLD-PCR enriches variant DNA 
sequences and redefines the sensitivity of genetic testing. Nat Med 14:579-84, 2008. 
 
34. 
Zuo Z, Chen SS, Chandra PK, et al. Application of COLD-PCR for improved detection of 
KRAS mutations in clinical samples. Mod Pathol 2009 May 8. [Epub ahead of print]. 
 
 
 


 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
18.2 
Carboplatin Dosing Worksheet 
 
18.3 
New York Heart Association Class 
 
18.4 
Proposed Rash Management Algorithm  
 
18.5 
Embedded Translational Medicine Studies 
 
18.6 
Central Radiology Review 
 
18.7 
Cancer Trials Support Unit (CTSU) Participation Procedures 
 
18.8 
SWOG S0819 Pathology Review Form 
 
 
 


 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
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 using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.1. 
 
All serious adverse events determined to be reportable to the Institutional Review Board 
responsible for the oversight of the patient must be reported according to local policy and 
procedures.  Documentation of this reporting should be maintained for possible inspection 
during quality assurance audits. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
(This includes all events that occur while on treatment or within 30 days of the last dose of 
protocol treatment.) 
 
Step 1: Determine whether the patient has received an investigational agent, commercial 
agent, or a combination of investigational and commercial agents. 
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (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 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. 
 
Sequential administration:   When a study includes an investigational agent(s) 
and a commercial agent(s) on the same study arm with sequential administration 
all expedited reporting of adverse events should follow the guidelines for the type 
of agent being given.  For example, if the patient begins the study on the 
investigational agent(s), then all expedited reporting of adverse events should 
follow guidelines for the investigational agent(s).  Once the patient begins 
receiving the commercial agent(s) then all expedited reporting of adverse events 
should follow the guidelines for commercial agent(s).   
 
Step 2: Identify the type of event using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE). The CTCAE provides descriptive terminology and a grading scale for 
each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home 
page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI has an Index 
to the CTCAE that provides help for classifying and locating terms.  
 
Step 3:  Grade the event using the NCI CTCAE version specified in the protocol for 
reporting serious adverse events. 
 
 


 
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Step 4: Determine if the adverse event is Expected or an Exception to Expedited 
Reporting.  Expected events are those that have been previously identified as resulting 
from administration of the agent and are listed in one of the following:   
 
 
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) for 
treatments using agents provided under an NCI-held IND, or an equivalent listing 
for treatments using agents provided under a Non-CTEP-held IND; located in 
Section 3.0 of the protocol. 
 
For treatments using commercial agents, the current CAEPR (Comprehensive 
Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), 
or other list of expected toxicities located in Section 3.0 of the protocol, or the drug 
package insert.   
 
Exception to Expedited reporting located in Section 16.1 f of the protocol. 
 
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 one of the areas outlined 
above. 
 
Step 5:  Determine whether the adverse event involved hospitalization or a prolongation of 
hospitalization (≥ 24 hours). 
 
Step 6:  Additionally, for commercial drugs, determine whether the adverse event is 
related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite.  Consult the appropriate table for expedited reporting 
criteria for commercial agent(s). 
 
NOTE:   Any event that occurs more than 30 days after the last dose of study agent and is 
attributed (possible, probable, or definite) to the study agent(s) must be reported according 
to the instructions above and as outlined in the appropriate table in Section 16.1. 
 


 
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18.2 
Carboplatin Dosing Worksheet 
 
 
PATIENT'S INITIALS  
 MEDICAL RECORD #  
 
 
 
 SWOG PATIENT #  
 
 
 
TO CALCULATE Creatinine Clearance (CrCl) from SERUM CREATININE: 
 
 
CrCl =  
(140 - age)      X     wt. in kg.* 
X 
0.85 (if female)  
 
72 X serum creatinine ** 
 
 
CrCl =  
(140 -       )      X      (            )  
X 
0.85 (if female) 
 
72 X  
 
 
 
TO CALCULATE CARBOPLATIN DOSE WITH CALVERT FORMULA: 
 
 
USE CALCULATED CREATININE CLEARANCE (AS ABOVE) TO SUBSTITUTE FOR GFR. 
 
(AUC) (GFR + 25) = CARBOPLATIN DOSE PER CYCLE IN mg 
 
(6) ( 
 
 +25) =   
 mg of carboplatin 
 
 
This is the TOTAL DOSE of carboplatin (not mg/m2). 
 
Please note that: GFR should NOT exceed 125 ml/min. Hence, the maximum total  
carboplatin dose should NOT exceed 900 mg for this study. 
 
* 
Use current (actual) weight. This should be actual weight but not exceed 140% of 
IBW.  
** 
Carboplatin dose should be calculated using a serum creatinine value obtained 
within 3 days prior to each course therapy.  In patients whose serum creatinine is < 
0.8 mg/dl, 0.8 mg/dl must be substituted in the Cockroft-Gault formula to calculate 
the estimated creatinine clearance for carboplatin dosing. 
 
NOTE:  PLEASE RETAIN ORIGINAL WORK SHEET as part of patient's PERMANENT 
RECORD.  COPIES MAY BE MADE FOR PHARMACY and/or NURSING RECORDS. 
 
 


 
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18.3 
New York Heart Association Class 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** 
At accustomed occupation or usual tasks. 
 


 
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18.4 
Proposed Rash Management Algorithm  
 
 
 
Macular Rash 
 
 
Pustular/Papular 
Rash 
Dry Skin 
 
Pruritis 
 
Ulcerative 
Lesions 
Grade 1 
Hydrocortisone 
cream 
Cleocin T Gel for 
limited single areas 
 
N/A 
N/A 
N/A 
Grade 2 
Cutivate Topical 
BID Medrol dose 
pack 
 
Minocin OR Bactrim 
DS 
Lotion applied 
BID 
Topical or 
Benadryl OR 
Atarax 
N/A 
 
Grade 3 
Medrol dose pack  
Consider 
dermatologic 
consultation 
 
Minocin OR Bactrim 
DS 
Consider 
dermatologic 
consultation 
Lotion applied 
TID 
Consider 
dermatologic 
consultation 
Benadryl OR 
Atarax 
Consider 
dermatologic 
consultation 
Vaseline or 
Silvadene 
Consider 
dermatologic 
consultation 
Grade 4 
Medrol dose pack  
Consider 
dermatologic 
consultation 
Minocin OR Bactrim 
DS 
Consider 
dermatologic 
consultation 
Lotion applied 
TID 
Consider 
dermatologic 
consultation 
Benadryl OR 
Atarax 
Consider 
dermatologic 
consultation 
Vaseline or 
Silvadene 
Consider 
dermatologic 
consultation 
 
Rhee J.  Oishi K. Garey J. Kim E.  Management of rash and other toxicities in patients treated with 
epidermal growth factor receptor-targeted agents.  Clin Colorectal Cancer.  2005 Nov:5 Suppl 
2:S101-6. 


 
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18.5 
Embedded Translational Medicine Studies-Integrated and Other 
 
In order to compare the results of the FISH and IHC assays outlined in Section 15.3 with 
other EGFR-related markers, other markers also will be assessed in specimens from this 
trial as integrated correlative studies. (e.g., tests that are clearly identified as part of the 
clinical trial from the beginning and intended to identify or validate assays or markers 
planned for future studies).   
 
Integrated Studies: 
 
EGFR Protein Expression by IHC: Diagnostic specimens will be sent to a central lab 
(University of Colorado-UCCC-under the direction of Dr. Wilbur Franklin) for assessment 
of EGFR protein expression by IHC using the DAKO EGFR scoring system (0-3+).  
EGFR-positive staining is defined as any IHC staining of tumor cell membranes above 
background level:  whether it is complete or incomplete circumferential staining.  Based on 
results from a recently completed prospective randomized Phase II study performed by 
OSI and UCCC in EGFR positive patients we expect similar properties to that of EGFR 
FISH as specified in Section 6.0.  
 
EGFR mutation analysis: EGFR activating mutations, which occur in 10-15% of 
unselected NSCLC patients in the USA, have proven to be associated with a high 
objective response rate (about 60%), but no large studies in the western countries have 
yet demonstrated a survival prolongation in EGFR mutated NSCLC patients (in contrast to 
Asian populations). EGFR mutation analysis will be performed in all patients included in 
this study and compared with EGFR FISH and IHC in an exploratory fashion. EGFR 
mutation analysis will be performed at UC Davis by Dr. Phil Mack using the DxS Scorpion 
method. 
 
Other Studies 
 
Proteomic analysis: Hirsch and collaborators have identified an “8-peak” serum 
proteomic classifier which is associated with good clinical outcomes after EGFR TKIs, 
both in 1st line therapy and 2nd line therapy.  (20)  In this proposal we will collect blood in 
all patients for further correlative studies and compare with the tissue-based marker 
analyses in an exploratory fashion.   
 
EGFR polymorphism studies:  analysis to be performed by Dr. Alex Adjei with the North 
Central Cancer Treatment Group (NCCTG) at Roswell Park Cancer Center. 
 
Angiogenesis-related markers: analysis will be performed at MD Anderson by Dr. John 
Heymach. 
 
1.1 
Correlative study design (to include methods for obtaining samples, administering 
forms, or performing radiologic studies): 
 
All registered and eligible patients will have either paraffin embedded blocks or 
unstained histological or cytological specimen(s) sent to the University of 
Colorado Cancer Center for EGFR FISH testing, IHC staining, KRAS and 
assessment of the other proposed EGFR-related biomarkers. These results will 
not be disclosed to the treatment sites.  
 
Blood (plasma and buffy coat) will be collected at the SWOG specimen bank for 
future research. 
 
 


 
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1.2 
Specific hypothesis (include relevant background studies): 
 
Based on studies and data reported above, this correlative science proposal has 
the following hypotheses: 
 
1. Cetuximab plus chemotherapy compared to chemotherapy alone will result in 
an improvement in progression-free survival (PFS) in EGFR FISH-positive 
patients. 
 
2. EGFR FISH will identify a cohort of patients deriving the greatest benefit as 
compared with the unselected population and IHC+ patients. 
 
3. EGFR FISH will compare favorably in exploratory analyses to other EGFR–
related biomarkers in identifying this cohort. 
 
1.3 
Statistical design (for each correlative study – include endpoints, sample size and 
monthly accrual rate): See above. 
 
Based on historical data, we assume that the proportion of IHC-positive patients is 
85% and we also assume that there are no EGFR FISH-positive/ IHC-negative 
patients.  Therefore, among 1,236 patients (80% of 1,546) with IHC and FISH 
results, it is expected that at least 1050 will be IHC positive and 618 will be both 
FISH positive and IHC positive.  The following table states the expected numbers 
of patients within each grouping: 
 
 
FISH/IHC unknown 
IHC- 
IHC+/FISH- 
IHC+/FISH+ 
# of patients 
310 
186 
432 
618 
 
The assumed median PFS in each of the prognostic/predictive grouping is 
included in the following table.  For the purpose of the following power calculations 
we have assumed that IHC status and FISH status are not prognostic. 
 
 
Control arm 
Experimental arm 
 
 
IHC-/FISH - 
IHC+/FISH- 
FISH+ 
Median PFS 
5.5 
6.6 
6.6 
7.3 
HR* 
-- 
1.10 
1.10 
1.33 
 * against control arm 
 
These values correspond to an improvement in median PFS overall of 20%, and 
an improvement of 22% in the IHC-positive group.  The second hypothesis in the 
unselected population is tested by an interaction test between EGFR FISH and 
treatment group.  Among the 1,236 patients assumed to have an EGFR result for 
IHC and FISH, this study has 49% power to detect an interaction between 
treatment arm and FISH status using a 1-sided 0.05 level test under the 
assumptions in the table above. 
 
The second hypothesis in the IHC+ population is tested by an interaction test 
between FISH and treatment group within the IHC+ population.  Among the 1,050 
patients assumed to be IHC+ and have a result for FISH, this study has 43% 
power to detect an interaction between treatment arm and FISH status using a 1-
sided 0.05 level test among IHC+ patients. 
 
Analysis of the other EGFR-related biomarkers will be exploratory in nature with 
the goal of augmenting the EGFR FISH analyses. 
 


 
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18.6 
Central Radiology Review 
 
All participants will undergo serial CT or MRI imaging:  
 
 
Baseline/pre-treatment 
 
Every 6 weeks until progression of disease (as determined by local site assessment) 
 
The same imaging modality MUST be used throughout the course of the trial.  The 
pre- and post-treatment CT or MRI images must be submitted to QARC for all study 
participants.  Imaging guidelines and image submission instructions are detailed 
below.    
 
Since real-time assessment and reporting of the central radiology review is not feasible, 
clinical management and treatment decisions will be made by the treating physician based 
on local site assessments and other clinically appropriate considerations.   
 
NOTE:  If a disease assessment is missed and/or delayed, if a scan is not done 
during a disease assessment for any reason; QARC must be notified of the missed 
and/or delayed disease assessment and the reason.  The notification must be 
submitted in writing to SWOG@qarc.org or FAXED to 401/753-7601. 
 
1.0 
Image Acquisition 
All study participants will undergo serial CT or MRI imaging to be done at baseline 
and every 6 weeks until progression of disease (as determined by local site 
assessment). 
 
1.1 
CT Imaging  
 
General CT imaging parameters are outlined below.  Additional scanning 
guidelines, per anatomic location, are detailed in the subsequent sections. 
 
 
Helical CT scanning is required; axial scanning cannot be used.   
 
Multi-detector scanning is preferred whenever possible, but single-
detector helical scanning can be used. 
o 
Single detector scanners: Pitch should be 1-1.5; images should 
be reconstructed at ≤ 5mm intervals in the axial plane. 
o 
Multi-detector scanners: It is strongly recommended that 
reconstruction be performed at the highest resolution possible (2 
mm or less), but will accept ≤ 5mm intervals. 
 
Each anatomic area (chest, abdomen, pelvis), scanner settings (kV, 
mAs) should be per institutional routine procedures. 
 
Choice of contrast agent should be according to local institutional 
routine.   
 
Contrast dose should be 100-150 mL. 
 
Injection rates should be 2 mL/sec minimum for chest and pelvis 
imaging and 3-5 mL/sec for abdominal imaging. 
 
18G IV is preferred for bolus rates of injection, especially for 
abdominal imaging. 
 
Central lines should not be used unless absolutely required due to 
lack of acceptable peripheral IV access.  Central lines should not be 
used with power injector unless specifically approved for that 
indication. 
 
a. 
Chest and Abdominal CT 
 
Scanning with IV contrast is preferred, but not required.  If IV contrast is 
used, pre-contrast imaging is not required.  Chest CT scanning should be 
performed per institutional standards, as 
 


 
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long as slice resolution requirements are met (< 5mm, preferably < 2mm).  
For contrast-enhanced imaging, a scan delay of approximately 20-30 
seconds is recommended.  If chest imaging is combined with abdominal 
(and pelvic) imaging, chest imaging should either be performed prior to 
abdominal imaging (non-contrast chest) or after abdominal (and pelvic) 
imaging. 
 
Abdominal imaging should be tailored for multi-phase liver imaging 
techniques.  Pre- and post-IV contrast imaging provides optimal evaluation 
of liver disease; IV contrast should be used whenever possible.  In cases 
when there is a contraindication to IV contrast, MRI is the preferred 
imaging modality for liver disease (if available). 
 
Recommended scanning protocol: Helical non-contrast imaging through 
the liver prior to contrast-enhanced imaging, followed by dual-phase 
(arterial and portal) contrast enhanced imaging is recommended.  Arterial 
phase scan delay time 20-30 seconds (or via bolus timing techniques per 
institutional routine).  Portal venous scan delay time approximately 60-75 
seconds.  Each vascular phase scan of the liver must be obtained in a 
single helical acquisition. 
 
1.2 
MRI Imaging 
 
General MRI imaging parameters are outlined below. 
 
Field strength of 1 tesla or greater. 
 
Imaging must be performed with a specialized torso array coil or other 
local coil combinations appropriate for body imaging.  Body coil for 
signal reception is not acceptable. 
 
Image slice thickness should be ≤ 7 mm. 
 
For contrast enhanced scanning, standard gadolinium chelates 
should be used at a dose of 0.1 mmol/kg to a maximum of 20mL.   
 
Injection rate should be 2cc/sec, and all injections must be followed 
by a saline flush of at least 20cc.  Peripheral 22-20G IV preferred. 
 
a. 
Chest and Abdominal MRI  
 
Axial imaging must be performed.  Imaging using T1W and T2W 
techniques is recommended.  Specific imaging sequences are per 
institutional standards.  Breath-held imaging is required.  Contrast 
enhanced imaging is not required, but is recommended for T1W 
imaging.  If chest MRI is performed in combination with abdominal 
imaging, chest imaging must precede abdominal imaging (i.e., 
non-contrast) or must be performed after abdominal imaging (i.e., 
delayed post-contrast). 
 
1.3 
PET/CT Imaging 
 
General PET/CT imaging parameters are outlined below: 
 
Only full-ring dedicated PET/CT scanners are acceptable. The CT of 
the PET/CT is used for attenuation correction of PET data and 
anatomic localization. CT settings should follow institutional guidelines 
(usually 120-140kV, at least 60mA).  


 
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 
A documented daily quality control procedure must be in place and 
records kept. 
 
Non-diabetic patients should fast for at least 4 hours prior to the scan.  
Plain (unflavored water) should be taken during the period of fasting 
and the uptake period to ensure good hydration. 
 
Diabetic patients should ideally be given a morning appointment. 
They should take their usual antidiabetic medication (oral or insulin) 
and eat a light meal (lighter than they normally would) on that 
morning. The time interval between that morning meal and PET/CT 
scan should be approximately 3-4 hours.     
 
Blood glucose of all patients should be measured on arrival and 
consideration given to rescheduling when the blood glucose level is 
higher than 200 mg/dl. Insulin should not be administered to reduce 
glucose level when the blood glucose is > 200 mg/dl at the time of 
arrival in the PET clinic.  
 
Oral diazepam may be given if desired to reduce brown fat uptake 
one hour prior to tracer injection.   
 
Oral diluted contrast (e.g., Gastografin or 2% barium sulfate) may be 
administered, according to institutional guidelines. Intravenous 
contrast may also be administered, provided this is done in a 
technique that avoids deterioration of the CT images by streak 
artifacts from high-concentration iv. contrast bolus.    
 
a. 
Scanning 
 
Administer 260 - 555 MBq (7-15mCi) 18F- FDG.  Emission part of 
the scan should start no earlier than 60 and no later than 80 
minutes after injection.  The exact same period of uptake must be 
used for staging and response scans – within 15 minutes. 
Perform attenuation corrected ‘half-body’ PET-CT scan to cover 
the area from the base of the skull to mid-thigh. This should be 
done with the arms above the head. Attenuation correction of 
PET emission data will be based on the low dose CT from the 
PET/CT. 
 
Acquisition should be performed using the institution’s standard 
protocol, i.e. with regard to time per bed position, 2D or 3D, CTAC 
parameters, reconstruction parameters etc. Images should be 
reconstructed using OSEM or a similar iterative reconstruction 
algorithm. Both attenuation-corrected and non attenuation-
corrected images should be reconstructed. 
 
2.0 
Image Submission 
 
Baseline scans and follow-up imaging at every 6 weeks for nine months and then 
every three months until progression or end of follow-up will be submitted via the 
AG Mednet service to QARC (the Quality Assurance Review Center). 
 
Instructions for Electronic Submission of Digital Exams to AG Mednet 
 
Exams must be submitted electronically via the AG Mednet service provided by 
SWOG. (Please note that while AG Mednet service is provided by SWOG, SWOG 
will not be responsible for the cost of the exams). Specific information about the 
imaging 
workflow 
and 
instructions 
can 
be 
found 
at 
http://www.agmednet.com/doc/TrialUserGuide.pdf.   
 


 
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Electronic Submission Set-up 
 
All participating sites will be provided with an AG Mednet Desktop Agent. The 
Desktop 
Agent 
can 
be 
ordered 
by 
e-mailing 
a 
request 
to 
agmednetadmin@swog.org.  AG Mednet will require the AG Mednet Desktop 
Agent Order Form to be faxed directly to AG Mednet at 617/674-8125 or 
submitted online at the link provided. After activating your desktop agent, sites will 
be able to submit images electronically, directly from a scanner or PACS, and also 
from a CD or file system.  
 
Although AG Mednet can accommodate transmission of both DICOM and 
non-DICOM files, the SWOG image repository can only accept DICOM files.  
All images must be submitted as DICOM files. 
 
NOTE: The person responsible for activating the desktop agent should be 
involved in submitting the exams as the desktop agent requires user specific log-
in verification.  All questions regarding AG Mednet agent use should be directed to 
888.9AGMEDNET, and hit 2 for the support option. 
 
Sites should contact AG Mednet at the time of IRB approval for AG Mednet 
enrollment to allow time for the Desktop Agent activation prior to patient 
registration. This contact is needed even if you are using AG Mednet for 
another SWOG trial.  Note that activation of the Desktop Agent may take 
several weeks. 
 
Exam Submission Process 
 
When submitting images, you will be required to follow the S0819 Image 
Submission protocol, which includes completing a transmittal form and de-
identifying the exam.  First import the exam from a CD or file system, PACS, or 
directly from the scanner.  Select the exam in your Desktop Agent worklist, assign 
it to the S0819 trial. 
 
To complete the Transmittal Form, select the form under the tasks column. 
Instructions for the form will be sent to your site at the time you enroll with AG 
Mednet.  The data from that transmittal form will be automatically integrated with 
the trial databases. 
  
To de-identify the exam, select de-identification in the task list.  The Agent will 
guide you through the proper blind encoding. If sites de-identify exams prior to 
importing, the AG Mednet Agent de-identification task will ensure the exam has 
been properly blind encoded.   
 
The final task in your workflow after completing the transmittal form and de-
identification is to upload the exam and associated information to SWOG.  This 
can be completed by selecting upload exam in the task list. 
 
Note: All questions regarding AG Mednet Agent use, transmittal forms, de-
identification or image submission through AG Mednet should be directed to 
888.9AGMEDNET, and hit 2 for the support option.  
 
3.0 
Central Radiology Review  
 
After registration, SWOG will provide QARC with the registration date and patient 
number, along with a blinded code indicating which reviewer will be assigned to 
each case.  This ensures that each reader reviews a balanced number of cases 
from each study arm.  An experienced radiologist will review each image for  


 
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assessment of progression of disease per RECIST criteria.  The same reviewer 
will read all study images of the study participant.  Data from local reviews will not 
be provided to the central reviewers in order to keep the central reviewers blinded 
to the results of the local investigator-assessed PFS.  The result of this read will 
constitute the definitive radiographic assessment of progression.  If assessment of 
progression for a participant based on central radiology review is earlier than the 
local investigator/site assessment progression, the date of central review disease 
progression will be the date of the exam that documented the progression per the 
central radiology review.  If central radiology review does not verify progression 
based on local radiographic assessment, QARC will continue to review any 
subsequent scans (if provided) to determine a later progression. 
 
The actual progression will be determined at the SWOG Statistical Center, using a 
composite of the QARC assessment, in conjunction with possible data on 
progression from other sources or symptomatic deterioration (see Section 10.6).  
Results of the central review will NOT be communicated to the local site.  
Decisions regarding clinical management of the patient will be made by the 
treating physician based on local site assessments/reviews and other clinical 
considerations. 
 
4.0 
Radiology Review Procedures 
 
 
Review of CT (or MRI) images will be performed using RECIST criteria. 
 
4.1  
Review of pre-treatment CT/MRI exam will be performed as follows:   
 
The reader will review all anatomic areas (chest, abdomen) imaged and available.  
The target lesions to be evaluated will be defined/determined by the 
review of the pre-treatment exam.  A maximum of 10 target lesions will be 
defined with a maximum of 5 in a single organ.  The 10 target lesions will 
be chosen with representation from all organs involved with the tumor.  
Additional significant non-target lesions and areas of non-measurable 
disease will be noted.  A screen capture of each target lesion, annotated 
with a pointer and a lesion reference number assigned to the target 
lesion, will be generated and archived.  This will be used on subsequent 
reads to ensure concordance of lesions on follow-up/post-treatment 
exams. Measurements will be made from the axial scan (generally the 
post contrast scan) that best demonstrates the lesion as distinct from 
background.  All measurements will be made by electronic calipers.  A 
screen capture of the actual measurement axis with calipers will be saved 
and archived with the exam permanently at QARC. 
 
4.2 
Review of post-treatment image exam(s) will be performed as 
follows:  The pre-treatment annotated exam and CRF will be reviewed to 
ensure lesion concordance.  Readers will review all images for the current 
time point prior to making measurements.  When performing lesion 
measurements on a scan from a given time point for a given target lesion, 
the previous measurement(s) of the specific target lesion will be reviewed 
to provide the reader with the previous axis and slice location for 
measurement.  Measurements will be made from the axial post-contrast 
image that best demonstrates the lesion as distinct from background.  
Longest axis diameter will be recorded.  Unless there is an obvious 
change in lesion shape, the reader will identify the slice on the current 
exam that best matches the lesion anatomy of the slice used for the prior 
measurement(s) and will choose an axis for diameter measurement that 
best 
approximates 
the 
axis 
used 
on 
the 
prior 


 
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measurement(s).  If there is an obvious change in lesion shape, a new 
axis that corresponds to the longest axis observed in the axial plane will 
be measured.  All measurements will be made by electronic calipers.  A 
screen capture of the actual measurement axis with calipers will be saved 
and archived with the exam permanently at QARC. 
 
 


 
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18.7 
Cancer Trials Support Unit (CTSU) Participation Procedures 
 
REGISTRATION/RANDOMIZATION 
  
Prior to the recruitment of a patient for this study, investigators must be registered 
members of the CTSU.  Each investigator must have an NCI investigator number and 
must maintain an “active” investigator registration status through the annual submission of 
a complete investigator registration packet (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure 
Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, 
NCI.  These forms are available on the CTSU registered member Web site or by calling 
the PMB at 240/276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. 
Eastern time. 
 
Each CTSU 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 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 at www.ctsu.org  
 
All forms and documents associated with this study can be downloaded from the S0819 
Web page on the CTSU registered member Web site (www.ctsu.org).  Patients can be 
registered only after pre-treatment evaluation is complete, all eligibility criteria have been 
met, and the study site is listed as ‘approved’ in the CTSU RSS.   
 
Requirements for S0819 site registration: 
 
 
CTSU IRB Certification 
 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
Pre-study requirements for patient enrollment on S0819 
 
 
Patient must meet all inclusion criteria, and no exclusion criteria should apply 
 
Patient has signed and dated all applicable consents and authorization forms 
 
All baseline laboratory tests and prestudy evaluations performed (including tumor and 
plasma samples) within the time period specified in the protocol.  
 
CTSU Procedures for Patient Enrollment 
 
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this study.  
OPEN can be accessed at open.ctsu.org or from the CTSU web site OPEN tab 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. Site staff 
should use the registration forms provided on the group or CTSU web site as a 
tool to verify eligibility. 
 
All 
patients 
have 
signed 
an 
appropriate 
consent 
form 
and 
HIPAA 
authorization form (if applicable).  
  
 


 
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Access requirements for OPEN: 
  
 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
 
To perform registrations, the site user must have been assigned the 'Registrar' 
role on the relevant Group or CTSU roster.  
 
To perform registrations on protocols for which you are a member of the Lead 
Group, you must have an equivalent 'Registrar' role on the Lead Group roster.  
Role assignments are handled through the Groups in which you are a member  
 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-
Lead Group registrations) you must have the role of Registrar on the CTSU roster. 
Site and/or Data Administrators can manage CTSU roster roles via the new Site 
Roles maintenance feature under RSS on the CTSU members' web site. This will 
allow them to assign staff the "Registrar" role.  
  
Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records.  
  
Further instructional information is provided on the CTSU web site OPEN tab or within the 
OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 
or ctsucontact@westat.com.  
 
DATA SUBMISSION AND RECONCILIATION 
 
 
1.  
All case report forms (CRFs) associated with this study must be downloaded from 
the S0819 Web page located on the CTSU registered member Web site 
(www.ctsu.org). Sites must use the current form versions and adhere to the 
instructions and submission schedule outlined in the protocol.   
 
2.  
Submit all completed CRFs (with the exception of patient enrollment forms), 
clinical reports, and transmittals directly to the SWOG Data Operations Center. 
The preferred method of sending data is via fax at 800-892-4007. Do NOT include 
a cover sheet for faxed data.  Do NOT send study data to the CTSU.  
 
3.  
The SWOG Data Operations Center will send query notices and delinquency 
reports directly to the site for reconciliation. Please send query responses and 
delinquent data to the SWOG Data Operations Center and do not copy the CTSU 
Data Operations. When faxing data include the query sheet that was originally 
sent from SWOG. 
 
4.  
Each site should have a designated CTSU Administrator and Data Administrator 
and must keep their CTEP IAM account contact information current. This will 
ensure timely communication between the clinical site and the SWOG data center. 
 
Special Materials or Substudies 
 
1.  
All specimens submitted for this study must be entered and tracked using the 
SWOG on-line Specimen Tracking System, as specified in protocol Section 15.0. 
 
2.  
You can also access the Tracking System from the CTSU Member Web Site. Go 
to the S0819 protocol page and click on the link provided under the Case Report 
Forms header. 
 


 
 
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Specimen Collection (Section 15.0) 
 
 
Collection and shipment kits will be provided by SWOG.  Ordering instructions 
are listed in protocol Section 15.1. 
 
Tumor and plasma specimen submissions are mandatory.  Additional 
information for tumor and plasma specimens submissions are outlined in 
Section 15.0 of the protocol.   
 
Radiology Review (Section 15.0) 
 
Submission of CT and/or MRI images is mandatory for central review. Please refer to 
Section 15.4 and Appendix 18.6 for more information. 
 
SERIOUS ADVERSE EVENT REPORTING 
 
1. 
CTSU sites must comply with the expectations of their local Institutional Review 
Board (IRB) regarding documentation and submission of adverse events.  Local 
IRBs must be informed of all reportable serious adverse reactions.  
 
2.  
CTSU sites will assess and report adverse events according to the guidelines and 
timelines specified in the protocol. You may navigate to the CTEP Adverse Event 
Report System (CTEP-AERS) from either the Adverse Events tab of the CTSU 
member homepage (www.ctsu.org) or by selecting Adverse Event Reporting 
Forms from the document center drop down list on the protocol number Web 
page.  
 
3.  
Do not send adverse event reports to the CTSU. 
 
4.  
Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, 
or ALL via the NCI/CTEP AML-MDS Report Form in lieu of CTEP-AERS. Submit 
the completed form and supporting documentation as outlined in the protocol.   
 
Drug Procurement (Section 3.0) 
 
Commercial agents: Bevacizumab (Avastin®), Carboplatin (CBDCA), Paclitaxel (Taxol®),  
Cetuximab (Erbitux®) 
 
Bevacizumab, Carboplatin, and Paclitaxel are commercially available and will not be supplied free 
of charge. 
  
Cetuximab will be provided free of charge by ImClone Systems, Inc/Bristol-Myers Squibb (BMS) 
and distributed by BMS. Ordering instructions can be found in Section 3.3.d of the protocol.  A 
copy of the Cetuximab Drug Request Form is available under Pharmacy Forms on the CTSU 
members’ web site.  
  
1. Information on drug formulation, procurement, storage and accountability, administration, and 
potential toxicities are outlined in Section 3.0 of the protocol.   
 
2. You may navigate to the drug forms by selecting Pharmacy under the Document folder on the 
S0819 Web page. 
 


 
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REGULATORY AND MONITORING 
 
Study Audit 
  
 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 
and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program 
(CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and 
study data validity, all protocols approved by NCI/CTEP that have patient enrollment through the 
CTSU are subject to audit. 
 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a 
Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through 
CTSU will become the responsibility of the Group receiving credit for the enrollment. For CTSU 
Independent Clinical Research Sites (CICRS), the CTSU will coordinate the entire audit process. 
 
For patients enrolled through the CTSU, you may request the accrual be credited to any Group for 
which you have an affiliation provided that Group has an active clinical trials program for the 
primary disease type being addressed by the protocol. Per capita reimbursement will be issued by 
the credited Group provided they have endorsed the trial, or by the CTSU if the Group has not 
endorsed the trial. 
 
Details on audit evaluation components, site selection, patient case selection, materials to be 
reviewed, site preparation, on-site procedures for review and assessment, and results reporting 
and follow-up can be found in the CTMB Monitoring Guidelines and are available for download 
from the CTEP web page 
http://ctep.cancer.gov/monitoring/guidelines.html. 
 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
 
The HIPAA Privacy Rule establishes the conditions under which protected health information may 
be used or disclosed by covered entities for research purposes. Research is defined in the Privacy 
Rule referenced in HHS 45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA 
guidelines are provided in the HIPAA Authorization Form located on the CTSU website.  
 
The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization 
to release Protected Health Information is NOT required from patients enrolled in clinical trials at 
non-US sites. 
 
Clinical Data System–Web (CDS-Web) Monitoring 
 
This study will be monitored by the Clinical Data System (CDS-Web). The sponsoring Group fulfills 
this reporting obligation by transmitting the CDS data collected from the study-specific case report 
forms, via the Web to the NCI Center for Biometrics (NCICB). Cumulative CDS data are submitted 
quarterly. 


 
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18.8 
SWOG S0819 Pathology Review Form 
 
SWOG S0819 Pathology Review Form 
SWOG Solid Tumor Biorepository 
 
SWOG ID #_____________  Patient Initials: ______(L, FM)  
Protocol of Interest: S0819f 
 
Pathology Diagnosis: _______________________________________________ 
 
Preliminary Data Specimen Submission: 
 
□Resected Tissue  
□Fine Needle Aspiration (FNA)  
□Core Biopsy 
 
Specimen Type Submitted: 
 
□Block – Surgical Pathology Number*   _______________________________ 
 
□Slides – Surgical Pathology Number*  _______________________________ 
  
Specimen Review 
 
Tumor Cells Available (PLEASE CHECK ONLY ONE): 
 
□Adequate (≥100 cells) 
□Inadequate (< 100 cells) 
 
* This is not the number given to the specimen from the Specimen Tracking System. 
 
____________________________________ 
 
_______________ 
Interpreted by   
 
 
 
 
Date 
 
 
NOTE: A copy of this form is to be submitted with the pathology report to the SWOG Solid Tumor 
Specimen Repository as outlined in Section 15.1. This form must also be faxed to the Data 
Operations Center at 800/892-4007 or 206/342-1680 locally. 
 
Comments: 
 
 
 

ICF_001.pdf: 
 
S0819 
 
Page 1 
 
Version Date 10/3/16 
 
 
 
Informed Consent Model for S0819 
 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  
(Institutions should attempt to use sections of this document that are in bold type in their 
entirety.)  Editorial changes to these sections may be made as long as they do not change 
information or intent.  If the institutional IRB insists on making deletions or more substantive 
modifications to the risks or alternatives sections, they may be justified in writing by the 
investigator and approved by the IRB.  Under these circumstances, the revised language, 
justification and a copy of the IRB minutes must be forwarded to the Southwest Oncology 
Group Operations Office for approval before a patient may be registered to this study.   
 
Please particularly note that the questions related to banking of specimens for future 
study are in bolded type and may not be changed in any way without prior approval 
from the Southwest Oncology Group Operations Office. 
Readability Statistics:   
 
Flesch Reading Ease  
60.2 (targeted above 55) 
Flesch-Kincaid Grade Level 8.3 (targeted below 8.5) 
 
 
Instructions and examples for informed consent authors are in [italics].  
 
A blank line,  __________, indicates that the local investigator should provide 
the appropriate information before the document is reviewed with the 
prospective research participant.  
 
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for 
a trial in which the local investigator is not a physician, another appropriate 
term should be used instead of "study doctor".  
 
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant.  
 
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational 
studies, any companies or grantors that are providing study support (these will 
be listed in the protocol's model informed consent form) and the Southwest 
Oncology Group.  
 
The "Southwest Oncology Group" must be listed as one of the parties that may 
inspect the research records in all protocol consent forms for which patient 
registration is being credited to the Southwest Oncology Group.  This includes  
 


 
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consent forms for studies where all patients are registered directly through the 
Southwest Oncology Group Data Operations Office, all intergroup studies for 
which the registration is being credited to the Southwest Oncology Group (whether 
the registration is through the SWOG Data Operations Office or directly through 
the other group), as well as consent forms for studies where patients are registered 
via CTSU and the registration is credited to the Southwest Oncology Group. 
 
When changes to the protocol require revision of the informed consent document,  
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are allowed 
as long as it is possible to determine during an audit that the patient signed the most 
current version of the consent form.  
 
*NOTES FOR LOCAL INVESTIGATORS:  
 
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  
It serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed consent 
form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is titled: "If You Have Cancer…What 
You Should Know about Clinical Trials".  This pamphlet may be ordered on the 
NCI Web site at http://cissecure.nci.nih.gov/ncipubs/details.asp?pid=1035 or call 
1-800-4- CANCER (1-800-422-6237) to request a free copy.  
 
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials. 
 
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  
 


 
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S0819, "A Randomized, Phase III Study Comparing Carboplatin/Paclitaxel 
or Carboplatin/Paclitaxel/Bevacizumab with or without Concurrent 
Cetuximab in Patients with Advanced Non-Small Cell Lung Cancer 
(NSCLC)" 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have advanced non-small cell lung 
cancer. 
 
Why is this study being done? 
 
The purpose of this study is compare the effects, good and/or bad, of cetuximab on lung 
cancer.  (7/29/09)  (sentences deleted 7/29/09) 
 
How many people will take part in the study? 
 
About 1,546 people will take part in this study.  
 
What will happen if I take part in this research study?   
 
Before you begin the study …  
 
You may need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if  
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
 Physical exam 
 Blood tests for blood counts, clotting time, electrolytes, kidney function, liver 
function 
 Urine tests 
 Brain CT/MRI 
 Other scans 
 EKG 
 


 
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During the study …  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you may need the following tests and procedures.  They are part of regular cancer care.  
 Physical exam about once every 3 weeks 
 Blood tests for blood counts, electrolytes, and kidney and liver function (about 
every 3 weeks) (7/12/10) 
 Urine tests for kidney function before every other treatment with bevacizumab 
(no urine test is necessary for patients not taking bevacizumab) 
 Other scans (about every 6 weeks) 
 
The following tests and procedures are being done to see how the study is affecting your body.  
Samples of your tumor tissue and blood are required for current scientific studies. (5/18/11) 
(paragraph updated 11/11/11) 
 A tissue specimen from the biopsy or surgery used to diagnose your cancer plus 
blood specimens from pre-treatment, at Week 7 and when you stop treatment will 
be sent to a special laboratory for testing to see if we can predict who should 
receive cetuximab as a part of their treatment in the future.  (5/18/11) The blood 
specimens will be taken at the same time that blood is taken for laboratory tests.  
Reports about research done with your specimens will not be given to you or 
your doctor.  These reports will not be put in your health record.  The research 
will not have an effect on your care. 
 
Treatment Plan 
 
You will be "randomized" to receive either chemotherapy without cetuximab or chemotherapy 
with cetuximab.  Randomization means that you are put into a group by chance.  A computer 
program will place you in one of the study groups.  Neither you nor your doctor can choose the 
group you will be in.  You will have an equal chance of being placed in either group to receive 
cetuximab or not.  (4/5/10) The decision about whether you will receive bevacizumab will be 
made by you and your doctor based on several considerations related to your health history.   
 
If you are in Group 1, you will have six three-week cycles of chemotherapy with paclitaxel, 
carboplatin and bevacizumab.  All of these are given by IV (through your veins).  You will 
receive the drugs once every 3 weeks.  You will receive the paclitaxel over 3 hours.  Right after 
that, you will receive the carboplatin over 30 minutes.  Finally, one hour after that, you will 
receive the bevacizumab.  The first time you receive bevacizumab, it will take about 90 minutes.  
Your doctor may be able to shorten this for future treatments if you tolerate it well.  The table 
below may help explain the treatment plan.  Total time to receive treatment in the first cycle will 
be about seven hours for all of the drugs.  Later cycles may be a bit shorter. 
 


 
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Drug 
Length of time - All Drugs are given by IV 
Frequency 
Paclitaxel 
Will take 3 hours. 
Every 3 
weeks  
Carboplatin 
Will begin right after paclitaxel and take 30 minutes. 
Every 3 
weeks  
Bevacizumab 
Will begin 1 hour after carboplatin and take 90 
minutes.  (The time may be shortened if you tolerate it 
well.) 
Every 3 
weeks  
 
After these six cycles of chemotherapy, you will continue bevacizumab without the other drugs 
on the same schedule as before. 
 
If you are in Group 2, you will have six three-week cycles of chemotherapy with paclitaxel and 
carboplatin.  These are given by IV (through your veins).  You will receive the drugs once every 
3 weeks.  You will receive the paclitaxel over 3 hours.  Right after that, you will receive the 
carboplatin over 30 minutes.  The table below may help explain the treatment plan.  Total time to 
receive treatment in the first cycle will be about three to four hours for both of the drugs.   
 
Drug 
Length of time - All Drugs are given by IV 
Frequency 
Paclitaxel 
Will take 3 hours. 
Every 3 
weeks  
Carboplatin 
Will begin right after paclitaxel and take 30 minutes. 
Every 3 
weeks  
 
If you are in Group 3, you will have six three-week cycles of chemotherapy with cetuximab, 
paclitaxel, carboplatin and bevacizumab.  All of these are given by IV (through your veins).  You 
will receive cetuximab once per week and the other drugs once every 3 weeks.   The cetuximab 
will take about one hour. After a one hour break, you will receive the paclitaxel over 3 hours.  
Right after that, you will receive the carboplatin over 30 minutes.  Finally, one hour after that, 
you will receive the bevacizumab.  The first time you receive bevacizumab, it will take about 90 
minutes.  Your doctor may be able to shorten this for future treatments if you tolerate it well.  
The table below may help explain the treatment plan.  Total time to receive treatment in the first 
cycle will be nine hours for all of the drugs.  Later cycles will take about seven hours to receive 
all of the drugs. 
 
Drug 
Length of time - All Drugs are given into a vein 
Frequency 
Cetuximab 
1 hour (the first dose will take 2 hours)  
Once per week 
Paclitaxel 
Will begin 1 hour after cetuximab and take 3 hours. 
Every 3 weeks  
Carboplatin 
Will begin right after paclitaxel and take 30 minutes. 
Every 3 weeks  
Bevacizumab Will begin 1 hour after carboplatin and take 90 minutes.  
(The time may be shortened if you tolerate it well.) 
Every 3 weeks  
 


 
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After these six cycles of chemotherapy, you will continue bevacizumab and cetuximab without the 
other drugs on the same schedule as before. 
 
If you are in Group 4, you will have six three-week cycles of chemotherapy with cetuximab, 
paclitaxel and carboplatin.  All of these are given by IV (through your veins).  You will receive 
cetuximab once per week and the other drugs once every 3 weeks.   The cetuximab will take 
about one hour. After a one hour break, you will receive the paclitaxel over 3 hours.  Right after 
that, you will receive the carboplatin over 30 minutes.  The table below may help explain the 
treatment plan.  Total time to receive treatment in the first cycle will be five to six hours for all 
of the drugs.   
 
Drug 
Length of time - All Drugs are given into a vein 
Frequency 
Cetuximab 
1 hour (the first dose will take 2 hours)  
Once per week 
Paclitaxel 
Will begin 1 hour after cetuximab and take 3 hours. 
Every 3 weeks  
Carboplatin 
Will begin right after paclitaxel and take 30 minutes. 
Every 3 weeks  
 
After these six cycles of chemotherapy, you will continue cetuximab without the other drugs on 
the same schedule as before. 
 
For all patients copies of all of your scans while you are in the study will be sent to a central 
location for review.  This central review will be done for research purposes only.  The result of 
the central review will not be sent back to you or your doctor. 
 
How long will I be in the study? 
 
If you are taking bevacizumab and/or cetuximab, you will be asked to take these study drugs as 
long as your disease does not get worse and the side effects are not too bad.  If you are receiving 
carboplatin and paclitaxel, your treatment on the study will end after six cycles.  After you are 
finished taking the study drugs, the study doctor will ask you to visit the office for follow-up 
exams every six weeks until your disease gets worse then every 3 months for the first year, and 
then every 6 months for up to 3 years.  During these visits, many of the scans and lab tests that 
you had during the study treatment will be repeated. 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drugs can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you. 


 
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The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
If you choose to take part in this study, there is a risk that: (Section updated 10/3/16) 
 You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
 You may be asked sensitive or private questions which you normally do not discuss 
The bevacizumab used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let 
you know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
 The study doctors do not know who will or will not have side effects. 
 Some side effects may go away soon, some may last a long time, or some may never go 
away. 
 Some side effects may interfere with your ability to have children. 
 Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
 Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
 The study doctor may be able to treat some side effects. 
 The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers 
know about. There might be other side effects that researchers do not yet know about. If 
important new side effects are found, the study doctor will discuss these with you. 
 
Risks and side effects related to carboplatin and paclitaxel include those that are: 
 
Likely: 
 Fatigue 
 Lowered white blood count, which may increase risk of infection  
 Lowered platelets, which may lead to an increase in bruising or bleeding 
 Lowered red blood cells, which may lead to anemia, tiredness, or shortness of breath  
 Loss of appetite and weight loss 
 Complete hair loss 
 Numbness, pain or tingling in fingers or toes  
 Pain in muscles and joints 
 Sores in mouth and throat (may result in difficulty swallowing), or on other parts of the 
body 


 
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 Changes in taste 
 Nausea, vomiting, diarrhea, constipation and abdominal pain 
 Weakness 
 Fever with or without chills 
 Headache 
 
Less likely: 
 Allergic reaction 
 Increase in temperature 
 Seizures 
 Infection 
 Vision problems 
 Ringing in the ears and hearing loss (hearing loss usually reversible but occasionally 
does not improve) 
 Dizziness 
 


 
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Rare but serious: 
 Inflammation of the lung (interstitial lung disease).  This could be life-threatening. 
 Inflammation of the liver, liver failure, death of liver tissue 
 Death of colon tissue 
 
Additional risks from bevacizumab: (Section Updated 10/3/16) 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, more than 20 and up to 100 may have: 
 High blood pressure which may cause headache or blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, from 4 to 20 may have: 
 Anemia which may require blood transfusion 
 Low white cell count that may increase the risk of infection  
 Infection, including collection of pus in the belly or rectum 
 Abnormal heartbeat which may cause palpitations or fainting 
 Pain in the belly, rectum, chest, joints, muscles, or tumor  
 Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or 
dehydration  
 Internal bleeding which may cause black tarry stool, blood in vomit, coughing 
up blood, or blood in urine 
 Bleeding from other sites, including the vagina or nose  
 Blockage of internal organs which may cause vomiting or inability to pass 
stool 
 Sores in the mouth  
 Allergic reaction during or after infusion of bevacizumab which may cause 
fever, chills, rash, itching, hives, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 Delay in healing of wounds or spontaneous opening of wounds  
 Weight loss, tiredness, or dizziness 
 Muscle weakness 
 Damage to organs which may cause loss of teeth or loss of motion 
 Headache 
 Numbness, tingling or pain in the fingers or toes  
 Hoarseness, stuffy nose, or cough  
 Dry skin 
 Swelling and redness of the skin or face 
 Blood clot in limbs or lungs which may cause swelling, pain, shortness of 
breath 
 Leakage of protein in the urine, which can rarely lead to damage to the kidney 


 
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RARE, AND SERIOUS 
In 100 people receiving bevacizumab, 3 or fewer may have: 
 Clots in the arteries, causing stroke (which may cause paralysis or weakness) 
or heart attack (which may cause chest pain or shortness of breath). This risk 
is significantly increased in patients who are elderly or with history of diabetes 
 Heart failure which may cause shortness of breath, swelling of ankles, and 
tiredness 
 Bowel perforation (a tear in the bowel) that can cause pain or bleeding and 
require surgery to repair  
 A tear or hole (fistula) in internal organs such as the nose, throat, lungs, 
esophagus, rectum, or vagina. These conditions  may cause serious infections 
or bleeding and require surgery to repair  
 Sores in the throat 
 Flesh-eating bacteria syndrome, an infection in the deep layers of skin  
 Bleeding in the tumor, brain, belly or lungs which may cause confusion, blood 
in stool or coughing up blood 
 Brain damage which may cause headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
 Kidney damage which may require dialysis 
 
Redness, pain or peeling of palms and soles 
Additional Notes: Risk in children or adolescents:  abnormal bone changes which 
may interfere with growth.  Risk in pre-menopausal women:  more likely to 
develop menopause when taking bevacizumab. 
 
Risks and side effects related to cetuximab include those that are: (updated 6/7/10) 
 
Likely: 
 Acne (updated 6/7/10) 
 Diarrhea (added 6/7/10) 
 Nausea or the urge to vomit (added 6/7/10) 
 Fatigue or tiredness (added 6/7/10) 
 Fever (added 6/7/10) 
 Headache or head pain (added 6/7/10) 
 Dry skin (added 6/7/10) 
 Skin rash with the presence of macules (flat discolored area) and papules (raised 
bump) (added 6/7/10) 
 
Less likely: (section updated 6/7/10) 
 Lack of enough red blood cells (anemia) 
 Inflammation (swelling and redness) of the skin of outer ear and canal 
 Noise in the ears, such as ringing, buzzing, roaring, clicking 
 Inflammation (swelling and redness) of the conjunctiva (the outermost layer of the eye 
and the inner surface of the eyelids).  Commonly called "pink eye". 


 
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 Dry eye 
 Inflammation (swelling and redness) of the middle layer of the eye (uvea) 
 Excessive tearing in the eyes 
 Belly pain 
 Inflammation (swelling and redness) of the lip 
 Constipation 
 Dry mouth 
 Heartburn 
 Irritation or sores in the lining of the mouth 
 Vomiting 
 Chills 
 Swelling of the arms and/or legs  
 Flu-type symptoms (including body aches, fever, chills, tiredness, loss of appetite, 
cough) 
 Reaction that can occur during or following infusion of the drug.  The reaction may 
include fever, chills, rash, low blood pressure, and difficulty breathing. 


 
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 Chest pain not heart-related 
 Allergic reaction by your body to the drug product that can occur immediately or may 
be delayed.  The reaction may include hives, low blood pressure, wheezing, swelling of 
the throat, and difficulty breathing. 
 Infection 
 Decreased number of a type of white blood cell (neutrophil/granulocyte) 
 Weight loss 
 Decrease in the total number of white blood cells (leukocytes) 
 Loss of appetite 
 Dehydration (when your body does not have as much water and fluid as it should) 
 Decreased blood level of calcium 
 Decreased blood level of magnesium (updated 6/7/10) 
 Joint pain 
 Back pain 
 Muscle pain 
 Fainting 
 Stuffy or runny nose, sneezing 
 Sudden constriction of the small airways of the lung that can cause wheezing and 
shortness of breath 
 Cough 
 Shortness of breath (updated 6/7/10) 
 Hoarseness 
 Hair loss 
 Loss of some or all of the finger or toenails 
 Increased skin sensitivity to sunlight  
 Itching 
 Area of bleeding within the skin causing a reddish purple discoloration 
 Sore or destruction of skin 
 Hives 
 Low blood pressure 
 Formation of a blood clot that plugs the blood vessel; blood clots may break loose and 
travel to another place, such as the lung 
 
Rare but Serious: 
 Inflammation of the lining of the brain and spinal cord (updated 6/7/10) 
 Serious, life-threatening allergic reaction requiring immediate medical treatment by 
your doctor.  The reaction may include extremely low blood pressure, swelling of the 
throat, difficulty breathing, and loss of consciousness. (updated 6/7/10) 
 Inflammation of the lungs that may cause difficulty breathing and can be life-
threatening (updated 6/7/10) 
 Fluid build-up in the lungs that is not due to a heart problem that can be life-
threatening (added 6/7/10) 
 Swelling and redness of the skin on the palms of the hands and soles of the feet (added 
6/7/10) 


 
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Additional risk information for protocols involving chemotherapy and cetuximab in 
patients with advanced NSCLC (section added 6/7/10) 
 In clinical trials involving patients with advanced, non-small cell lung cancer, the 
combination of cetuximab and chemotherapy may increase the risk of life-
threatening complications, some of which may be fatal, in elderly patients (65 
years old or more), particularly those with pre-existing cardiac disease. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a 
baby while on this study.  It is important you understand that you need to use birth control 
while on this study and for 6 months after your last dose of bevacizumab or for 3 months 
after your last dose of cetuximab (whichever is later).  Check with your study doctor about 
what kind of birth control methods to use and how long to use them.  Some methods might 
not be approved for use in this study.  
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While doctors hope 
that this treatment will be more useful against cancer compared to the usual treatment, 
there is no proof of this yet. We do know that the information from this study will help 
doctors learn more about these drugs as a treatment for cancer.  This information could 
help future cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
 Getting treatment or care for your cancer without being in a study 
 Taking part in another study 
 Getting no treatment 
 Getting comfort care, also called palliative care.  This type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer.  It does 
not treat the cancer directly, but instead tries to improve how you feel.  Comfort 
care tries to keep you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 


 
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Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 The Southwest Oncology Group 
 Qualified representatives of Bristol Myers Squibb and ImClone (7/29/09) 
 The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
 The Cancer Trials Support Unit (CTSU), a service sponsored by the National Cancer 
Institute (NCI) to provide greater access to cancer trials. 
 
 [Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
Administration of the drug will be (provided free of charge/charged in the usual way).  The parts 
of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate).  (local institutions must choose the option that best fits the 
hospital's situation) 
 
Bristol Myers Squibb/ImClone will provide you with cetuximab free of charge while you are 
participating in this study.  (7/29/09) 
 
Carboplatin, bevacizumab and paclitaxel are commercially available. 
 


 
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You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout/payingfor/how-
insurance-companies-decide.  (updated 5/1/13) You can print a copy of the "Clinical Trials and 
Insurance Coverage" information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.   
 
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
A Data and Safety Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study.  We will tell you about important new information 
from this or other studies that may affect your health, welfare, or willingness to stay on this 
study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 


 
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For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
 
You may also call the Operations Office of the NCI Central Institution Review Board (CIRB) at 
888-657-3711 (from the Continental US only).  [*Only applies to sites using the CIRB.] 
 
Please note:  This section of the informed consent form is about additional research 
studies that are being done with people who are taking part in the main study.  You 
may take part in these additional studies if you want to.  You can still be a part of the 
main study even if you say 'no' to taking part in any of these additional studies. 
 
You can say "yes" or "no" to each of the following studies.  Please mark your choice 
for each study.   
 
1. 
Future Contact 
I agree to allow my study doctor, or someone approved by my study doctor, to contact me 
regarding future research involving my participation in this study.  
Yes 
No 
 
2. 
Storage and Use of Specimens for Future, Unspecified Research 
 
This study requires submission of tissue from the biopsy (or surgery) used to diagnose lung 
cancer. 
It also requires submission of blood specimens at pre-treatment, at 7 weeks after starting 
treatment and at the end of treatment. (11/11/11) This will be used for special testing as outlined 
earlier. 
(section deleted 11/11/11) 
We would like to keep some of the specimens that are left over for future research. If you agree, 
these specimens will be kept and may be used in research to learn more about cancer and other 
diseases. Please read the information sheet called "How are Specimens Used for Research" to 
learn more about tissue research.  
The research that may be done with your specimens is not designed specifically to help you. It 
might help people who have cancer and other diseases in the future.  
Reports about research done with your specimens will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care.  


 
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Things to Think About  
The choice to let us keep the leftover specimens for future research is up to you. No matter what 
you decide to do, it will not affect your care.  
If you decide now that your specimens can be kept for research, you can change your mind at 
any time. Just contact us and let us know that you do not want us to use your specimens. Then 
any specimens that remain will no longer be used for research.  
In the future, people who do research may need to know more about your health. While the 
Southwest Oncology Group may give them reports about your health, it will not give them your 
name, address, phone number, or any other information that will let the researchers know who 
you are.  
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families). Even if your specimens are used for this kind of research, the results will not be put in 
your health records.  
Your specimens will be used only for research and will not be sold. The research done with your 
specimens may help to develop new products in the future.  
Benefits   
The benefits of research using specimens include learning more about what causes cancer and 
other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, circle 
"Yes" or "No."  If you have any questions, please talk to your doctor or nurse, or call our 
research review board at IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1.  
My specimens may be kept for use in research to learn about, prevent, treat or cure 
cancer.  
Yes 
No 
2.  
My specimens may be kept for use in research about other health problems (for 
example: diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 


 
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3.  
Someone may contact me in the future to ask me to allow other uses of my 
specimens.  
Yes 
No 
If you decide to withdraw your specimens from a Southwest Oncology Group Specimen 
Repository in the future, a written withdrawal of consent should be submitted through 
your study doctor to the Southwest Oncology Group Operations Office.  Please designate in 
the written withdrawal whether you would prefer to have the specimens destroyed or 
returned to the study doctor. 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
 For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
 For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor. 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant (or legally authorized representative)  
 (5/1/13) 
 
Date _____________________________________ 
 


 
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How are Specimens Used for Research? 
 
Where do specimens come from? 
 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  People 
who are trained to handle specimens and protect donors' rights make sure that the highest standards of 
quality control are followed by the Southwest Oncology Group.  Your doctor does not work for the Southwest 
Oncology Group, but has agreed to help collect specimens from many patients.  Many doctors across the 
country are helping in the same way.   
 
Why do people do research with specimens? 
 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to treat 
it, and how to cure it.  Research using specimens can also answer other health questions.  Some of these 
include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
 
What type of research will be done with my specimen? 
 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find diseases.  
Others may develop new ways to treat or even cure diseases.  In the future, some of the research may help 
to develop new products, such as tests and drugs.  Some research looks at diseases that are passed on in 
families (called genetic research).  Research done with your specimen may look for genetic causes and signs 
of disease. 
 
How do researchers get the specimen? 
 
Researchers from universities, hospitals, and other health organizations conduct research using specimens.  
They contact the Southwest Oncology Group and request samples for their studies.  The Southwest Oncology 
Group reviews the way that these studies will be done, and decides if any of the samples can be used. The 
Southwest Oncology Group gets the specimen and information about you from your hospital, and sends the 
specimen samples and some information about you to the researcher.  The Southwest Oncology Group will 
not send your name, address, phone number, social security number or any other identifying information to 
the researcher. 
 
Will I find out the results of the research using my specimen? 
 
You will not receive the results of research done with your specimen.  This is because research can take a 
long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, but 
they may be helpful to people like you in the future. 
 
Why do you need information from my health records? 
 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to the 
researcher may include your age, sex, race, diagnosis, treatments and family history.  This information is 
collected by your hospital from your health record and sent to the Southwest Oncology Group.  If more 
information is needed, the Southwest Oncology Group will send it to the researcher. 
 
Will my name be attached to the records that are given to the researcher? 
 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you 


 
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How could the records be used in ways that might be harmful to me? 
 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such as 
AIDS or cancer).  The results of genetic research may not apply only to you, but to your family members too.  
For disease caused by gene changes, the information in one person's health record could be used against 
family members. 
 
How am I protected? 
 
The Southwest Oncology Group is in charge of making sure that information about you is kept private.  The 
Southwest Oncology Group will take careful steps to prevent misuse of records.  Your name, address, phone 
number and any other identifying information will be taken off anything associated with your specimen before 
it is given to the researcher.  This would make it very difficult for any research results to be linked to you or 
your family.  Also, people outside the research process will not have access to results about any one person 
which will help to protect your privacy. 
 
What if I have more questions? 
 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number).