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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                       |                                                                                                                            |
| 1.0                          | OBJECTIVES .                                                                                                               |
| 1.1                          | Primary Objective                                                                                                          |
| 1.2                          | Secondary Objectives .                                                                                                     |
| 1.3                          | Tertiary Objectives                                                                                                        |
| 2.0                          | BACKGROUND                                                                                                                 |
| 3.0                          | DRUG INFORMATION .                                                                                                         |
| 3.1                          | Bevacizumab (rhuMAb VEGF) (Avastin®) (NSC #704865) ................................................... 14                  |
| 3.2                          | Carboplatin (CBDCA) (NSC-241240) .                                                                                         |
| 3.3                          | Cetuximab (IMC-C225) (Erbitux®) (NSC-714692) .......................................................................... 28 |
| 3.4                          | Paclitaxel, Taxol® (NSC-673089)                                                                                            |
| STAGING CRITERIA             |                                                                                                                            |
| 4.0                          |                                                                                                                            |
| 5.0                          | ELIGIBILITY CRITERIA .                                                                                                     |
| 5.1                          | Disease Related Criteria .                                                                                                 |
| 5.2                          | Clinical/Laboratory Criteria                                                                                               |
| 5.3                          | Regulatory Criteria                                                                                                        |
| 6.0                          | STRATIFICATION FACTORS                                                                                                     |
| 6.1                          | Bevacizumab–APPROPRIATE Status:  Yes versus No.                                                                            |
| 6.2                          | Smoking Status .                                                                                                           |
| 6.3                          | Stage                                                                                                                      |
| 7.0                          | TREATMENT PLAN .                                                                                                           |
| 7.1                          | Good Medical Practice                                                                                                      |
| 7.2                          | Pre-medication .                                                                                                           |
| 7.3                          | T Treatment                                                                                                                |
| 7.4                          | Precautions                                                                                                                |
| 7.5                          | Guidelines for Carboplatin Administration                                                                                  |
| 7.6                          | Hematologic Requirements for Day 1 of Each Cycle .                                                                         |
| 7.7                          | Supportive Care                                                                                                            |
| 7.8                          | Criteria for Removal from Protocol Treatment .                                                                             |
| 7.9                          | Discontinuation of Treatment .                                                                                             |
| 7.10                         | Follow Up Period .                                                                                                         |
| 7.11                         | Radiology Review .                                                                                                         |
| 8.0                          | TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ............................... 53                                     |
| 8.1                          | NCI Common Terminology Criteria for Adverse Events (CTCAE)                                                                 |
| 8.2                          | General Dose Modifications .                                                                                               |
| 8.3                          | Dose Modifications for Carboplatin and Paclitaxel                                                                          |
| 8.4                          | Dose Modifications for Cetuximab .                                                                                         |
| 8.5                          | Dose Modifications for Bevacizumab                                                                                         |
| 8.6                          | GG                                                                                                                         |
| 8.7                          | G-CSF Dose Modifications                                                                                                   |
| 8.8                          | Dose Modifications for Non-Hematologic Toxicity                                                                            |
| Dose Modification Contacts . |                                                                                                                            |
| 8.9                          |                                                                                                                            |
| 8.10                         | Adverse Event Reporting                                                                                                    |  
Page 2  
| Version Date 10/3/16                                                                                                    |                                                                                                                                                       |    |
|-------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|----|
| 9.0                                                                                                                     | STUDY CALENDAR                                                                                                                                        |    |
| Study Calendar - ARM 1a - Chemotherapy plus Bevacizumab without Cetuximab ........ 63                                   |                                                                                                                                                       |    |
| 9.1                                                                                                                     | ARM 1b - Chemotherapy without Cetuximab.                                                                                                              |    |
| 9.2                                                                                                                     | ARM 2a - Chemotherapy plus Bevacizumab with Cetuximab ................................................. 67                                            |    |
| 9.3                                                                                                                     |                                                                                                                                                       |    |
| 9.4                                                                                                                     | ARM 2b - Chemotherapy with Cetuximab                                                                                                                  |    |
| 10.0                                                                                                                    | CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS                                                                                                      |    |
| 10.1                                                                                                                    | Measurability of Lesions                                                                                                                              |    |
| 10.2                                                                                                                    | Objective Status .                                                                                                                                    |    |
| 10.3                                                                                                                    | Best Response                                                                                                                                         |    |
| 10.4                                                                                                                    | Performance Status .                                                                                                                                  |    |
| 10.5                                                                                                                    | Progression-Free Survival (Central-Review Based) .                                                                                                    |    |
| 10.6                                                                                                                    | Progression-Free Survival                                                                                                                             |    |
| 10.7                                                                                                                    | Time to Death                                                                                                                                         |    |
| 1.0                                                                                                                     | STATISTICAL CONSIDERATIONS                                                                                                                            |    |
| 11.1                                                                                                                    | Primary Endpoint                                                                                                                                      |    |
| 11.2                                                                                                                    | Secondary Endpoints                                                                                                                                   |    |
| 1.3                                                                                                                     | H-Score                                                                                                                                               |    |
| 1.4                                                                                                                     | Sample Size With Power Justification .                                                                                                                |    |
| Analysis Plan Including Plans for Formal Interim Analysis .......................................................... 77 |                                                                                                                                                       |    |
| 1.5                                                                                                                     |                                                                                                                                                       |    |
| 1.6                                                                                                                     | Amendment to design                                                                                                                                   |    |
| 1.7                                                                                                                     | Accrual Information                                                                                                                                   |    |
| 1.8                                                                                                                     | Data and Safety Monitoring Committee ............................................................................................................. 82 |    |
| 12.0                                                                                                                    | DISCIPLINE REVIEW                                                                                                                                     |    |
| 13.0                                                                                                                    | REGISTRATION GUIDELINES                                                                                                                               |    |
| 13.1                                                                                                                    | Registration Timing                                                                                                                                   |    |
| 13.2                                                                                                                    | OPEN Registration Requirements .                                                                                                                      |    |
| 13.3                                                                                                                    | Registration Procedures                                                                                                                               |    |
| 13.4                                                                                                                    | Registration Exceptions                                                                                                                               |    |
| 14.0                                                                                                                    | DATA SUBMISSION SCHEDULE .                                                                                                                            |    |
| 14.1                                                                                                                    | DATA SUBMISSION REQUIREMENTS .                                                                                                                        |    |
| 14.2                                                                                                                    | Master Forms .                                                                                                                                        |    |
| 14.3                                                                                                                    | DATA SUBMISSION Procedures .                                                                                                                          |    |
| Data Submission Overview and Timepoints                                                                                 |                                                                                                                                                       |    |
| 14.4                                                                                                                    |                                                                                                                                                       |    |
| 15.0                                                                                                                    | SPECIAL INSTRUCTIONS                                                                                                                                  |    |
| 15.1                                                                                                                    | Required Tissue Specimens for EGFR FISH and KRAS                                                                                                      |    |
| 15.2                                                                                                                    | Required Plasma and Buffy Coat for Translational Medicine and Optional Banking ..... 89                                                               |    |
| 15.3                                                                                                                    | Integral Translational Medicine Studies                                                                                                               |    |
| 15.4                                                                                                                    | RAdiology Review .                                                                                                                                    |    |
| 16.0                                                                                                                    |                                                                                                                                                       |    |
| 16.1                                                                                                                    | Adverse Event Reporting Requirements                                                                                                                  | 93 |
| 17.0                                                                                                                    | BIBLIOGRAPHY                                                                                                                                          |    |
| 18.0                                                                                                                    | APPENDIX                                                                                                                                              |    |
| 18.1                                                                                                                    | Determination of Expedited Adverse Event Reporting Requirements .................................... 99                                               |    |
| 18.2                                                                                                                    | Carboplatin Dosing Worksheet .                                                                                                                        |    |
| 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                                                                                                                              |    |
| Cancer Trials Support Unit (CTSU) Participation Procedures .............................................. 112           |                                                                                                                                                       |    |
| 18.7                                                                                                                    |                                                                                                                                                       |    |
| 18.8                                                                                                                    | SWOG S0819 Pathology Review Form .                                                                                                                    |    |  
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
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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
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participants

ALLIANCE/Alliance for Clinical Trials in Oncology ECOG-ACRIN/ECOG-ACRIN Cancer Research Group NRG/NRG Oncology SWOG/SWOG
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.  
| To submit site registration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | For patient enrollments:                                                                     | Submit study data directly to the                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| documents:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 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 |                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |  
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS
AND CONTACT INFORMATION  

Cetuximab
1.1 Primary Objective  
1.0 OBJECTIVES
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.
Rationale for selected approach and trial design.  
2.0 BACKGROUND
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 cetuximabbased therapy in NSCLC.  
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 (paclitaxelcarboplatin) 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 FISHnegative 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.  
  
  
Figure 1: S0342 Phase II Selection Design Schema 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.
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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 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  Mutant   | p-value   |          |      |
|----------------------------------------------------------------------|-----------|----------|------|
| N=28                                                                 | N=17      |          |      |
| Response                                                             | 5 (18%)   | 5 (29 %) | 0.47 |
| Disease control                                                      | 17 (61%)  | 12 (71%) | 0.54 |
| S0342 Analysis for Response: Tissue + Plasma   Wild type  Mutant     | p-value   |          |      |
| N=83                                                                 | N=27      |          |      |
| Response                                                             | 22 (27%)  | 9 (33 %) | 0.62 |
| Disease control                                                      | 61 (73%)  | 19 (70%) | 0.81 |
|                                                                      |           |          |      |  
  
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  
  
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.
privileged communication
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 FISHpositive 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 cetuximabchemotherapy 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 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 "bevacizumabappropriate" 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    |
privileged communication
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. 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.
privileged communication
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.  
| 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                                                    | Rare but |
| (<=20%)                                                                             | Serious (<3%)                                                  |          |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                         | Anemia (Gr 3)                                                  |          |
| Blood and  lymphatic system  disorders - Other  (renal thrombotic  microangiopathy) |                                                                |          |
| Febrile                                                                             | Febrile neutropenia                                            |          |
| neutropenia                                                                         | (Gr 3)                                                         |          |  
**Version 2.4, May 23, 20161**  
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| Version Date 10/3/16                                                                                                               |                                                                     |
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| 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                                                                                                                   | Gastrointestinal                                                    |
| hemorrhage5                                                                                                                        | hemorrhage5 (Gr 2)                                                  |
| Gastrointestinal  obstruction6                                                                                                     | Gastrointestinal  perforation7  Gastrointestinal  8  ulcer          |
| 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                                                                                                                   | Infusion related                                                    |
| reaction                                                                                                                           | reaction (Gr 2)                                                     |
| Non-cardiac chest                                                                                                                  | Non-cardiac chest                                                   |
| pain                                                                                                                               | pain (Gr 3)                                                         |
| Pain                                                                                                                               | Pain (Gr 3)                                                         |
| HEPATOBILIARY DISORDERS                                                                                                            | Gallbladder  perforation                                            |
| IMMUNE SYSTEM DISORDERS Allergic reaction                                                                                          | Allergic reaction (Gr  2)                                           |
| Anaphylaxis                                                                                                                        |                                                                     |  
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| 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 (Gr 3) Blood bilirubin  Blood bilirubin  increased  increased (Gr 2)  Creatinine  increased  Neutrophil count decreased Neutrophil count  decreased (Gr 3) Platelet count  Platelet count  decreased  decreased (Gr 4) Weight loss Weight loss (Gr 3) White blood cell  White blood cell  decreased 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 weaknessAspartate  aminotransferase  increased |                   |  
| 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)           |  
| 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  (tracheoesophageal  fistula)                                                                                                                      |                                                                             |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Erythroderma  Palmar-plantar  erythrodysesthe sia syndrome  Pruritus | Pruritus (Gr 2)                                                             |
| Rash maculopapular                                                                                                                      | Rash maculopapular (Gr 2)                                                                             |
| Urticaria                                                                                                            | Urticaria (Gr 2)                                                            |
| VASCULAR DISORDERS Hypertension                                                                                      | Hypertension (Gr 3)                                                         |
| Thromboembolic                                                                                                       | Thromboembolic                                                              |
| event                                                                                                                | 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. |  
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.  
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 folliclestimulating 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 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 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 altered mental status, seizure and cortical visual deficit. HTN is a 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. 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 halflife 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. 13.6%).  
Fertility and Pregnancy: Clinical data are lacking regarding the immediate or longterm 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.
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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. 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.
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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.  
3.2 Carboplatin (CBDCA) (NSC-241240)
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a. description

Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an analog of cisplatin, producing intrastrand DNA cross-links.
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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.
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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 postdistributional 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). 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.
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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)
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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.
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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 posttreatment sera using a double antigen radiometric assay. The incidence of an anticetuximab 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 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  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  Adverse Events with Possible   Relationship to Cetuximab   (CTCAE 4.0 Term)  [n= 2282]  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               |          |  
| 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)   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 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 maculopapular                     |
| Skin ulceration Urticaria                    | Urticaria           |
| VASCULAR DISORDERS Hypotension               | Hypotension         |
| Thromboembolic event                         | Thromboembolic 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:
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blood and lymphatic system disorders

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 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, cetuximabchemotherapy 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.  
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.
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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 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 2C to 8C (36F to 46F). DO NOT FREEZE. Increased particulate formation may occur at temperatures at or below 0C. This product contains no preservatives.  
Preparations of cetuximab in infusion containers are chemically and physically stable for up to 12 hours at 2C to 8C (36F to 46F) and up to 8 hours at controlled room temperature (20C to 25C; 68F to 77F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2C to 8C. 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 0.22micrometer 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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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.  
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.  
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.
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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.
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3.4 paclitaxel taxol (nsc-673089) a.

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), lightheadedness, 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.
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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. 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 225°C. Based on stability data for Taxol® made from either natural or semisynthetic 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.
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4.0 staging criteria

Patients must have Stage IV disease as outlined below (AJCC Cancer Staging Manual, 7th Edition, 2009):
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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
* 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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swog patient no. patient's initials

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.  
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.  
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.  
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].  
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 sideeffect 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.
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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.
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.):  
6.0 STRATIFICATION FACTORS
≥ 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 intraabdominal 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 "bevacizumabAPPROPRIATE" cohort.  
6.2 Smoking Status Smoking status: current or former (no smoking for 1 year or more) versus never (less than 100 cigarettes lifetime).
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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.
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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. 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
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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.
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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.  
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.
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).
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b. arm 2-chemotherapy with cetuximab

Based on stratification, patients will be treated as "bevacizumab-APPROPRIATE" or "bevacizumab-INAPPROPRIATE ".  
1. Arm 2a-Bevacizumab-APPROPRIATE (see Section 6.1 for definitions)
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treatment consists of up to

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.  
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 CockroftGault 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)  
|                | 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                             |             |                 |
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treatment consists of up to

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.  
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 CockroftGault 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).
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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:
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crci = (140 - age)

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.
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see appendix 18.2 for carboplatin

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.
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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
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will transmit the results to

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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8.2 general dose modifications note

8.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS  
| 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. |               |              |     |  
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. 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.  
Dose adjustments of carboplatin, paclitaxel, cetuximab and bevacizumab will be made based on the occurrence and extent of toxicity.  
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 b. Routine toxicity reporting 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.
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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.  
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.  
| 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. |             |              |           |  
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.  
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.
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g. hyperglycemia - carboplatin and

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.  
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.  
| 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.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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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.
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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.   |
|------------------------------------------|  
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.
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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.  
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.
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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,                                                                                         | 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 or  Acute infusional  reactions/ cytokine  release syndrome  Grade 2 (if new or  worsened since  bevacizumab  therapy)  Discontinue bevacizumab  Grade 3-4 Discontinue bevacizumab  Reversible Posterior Leukoencephalopathy  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                                                                                                             |                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |