Randomized Phase II Study of Weekly Irinotecan/Carboplatin (ICb) With or Without Cetuximab (Erbitux) in Patients With Metastatic Breast Cancer
Phase: PHASE2
Conditions: Metastatic Breast Cancer
Sponsor: US Oncology Research

 
CONFIDENTIAL 
Information and data included in this protocol contain trade secrets and privileged or confidential information which is 
the property of USOR, Bristol-Myers Squibb, and Pfizer, Inc. No person is authorized to make it public without written 
permission of USOR, Bristol-Myers Squibb, and Pfizer, Inc. These restrictions on disclosure will apply equally to all 
future information supplied to you, which is indicated as privileged or confidential. This material may be disclosed to 
and used by your staff and associates as may be necessary to conduct this clinical study. 
1 
 
Randomized Phase II Study of Weekly Irinotecan/Carboplatin 
(ICb) with or without Cetuximab (Erbitux) in Patients with 
Metastatic Breast Cancer 
PROTOCOL 04-070 
 
Study Investigator: 
Joyce O’Shaughnessy, M.D. 
3535 Worth Street 
Dallas, TX 75246 
Phone: (214) 370-1795 
Fax: (214) 370-1850 
Supported By: 
Bristol-Myers Squibb 
777 Scudders Mill Road 
Plainsboro, NJ 08536 
Phone: (609) 897-2000 
Pfizer, Inc. 
US Medical Oncology 
235 East 42nd Street 
New York, NY 10017 
Phone: (212) 733-2323  
Date: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Administrative change: 
April 18, 2005 
July 05, 2005 
December 01, 2005 
June 08, 2006 
September 14, 2006 
June 27, 2008 
April 12, 2010 
 
 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
2
Table of Contents 
ABBREVIATIONS ....................................................................................................................................6 
SYNOPSIS................................................................................................................................................7 
PART I – CLINICAL TRIAL PROTOCOL ................................................................................................11 
1 
INTRODUCTION.............................................................................................................................11 
1.2 
BACKGROUND ON BREAST CANCER ..................................................................................................11 
1.1.1 
Chemotherapy in Breast Cancer ........................................................................................................ 11 
1.2 
BACKGROUND ON IRINOTECAN..........................................................................................................12 
1.3 
BACKGROUND ON CARBOPLATIN.......................................................................................................14 
1.3.1 
Carboplatin in the Treatment of Metastatic Breast Cancer................................................................ 14 
1.4 
BACKGROUND ON IRINOTECAN AND CARBOPLATIN ..........................................................................14 
1.5 
BACKGROUND ON ERBITUX (CETUXIMAB) ........................................................................................15 
1.5.1 
Human Pharmacokinetics.................................................................................................................. 16 
1.5.2 
Immunogenicity................................................................................................................................. 16 
1.5.3 
Clinical Studies of Cetuximab in Colorectal Cancer: Efficacy.......................................................... 17 
1.5.3.1 
Randomized, Controlled Trials.................................................................................... 17 
1.5.3.2 
Single-Arm Trials......................................................................................................... 18 
1.5.3.3 
EGFR Expression and Response.................................................................................. 19 
1.5.4 
Safety of Cetuximab in Clinical Studies............................................................................................ 19 
1.5.4.1 
Anticipated Adverse Events.......................................................................................... 19 
1.5.4.2 
Infusion Reactions........................................................................................................ 22 
1.5.4.3 
Pulmonary Toxicity...................................................................................................... 22 
1.5.4.4 
Dermatologic Toxicity ................................................................................................. 22 
1.6 
RATIONALE........................................................................................................................................23 
2 
TRIAL OBJECTIVES......................................................................................................................23 
2.1 
PRIMARY OBJECTIVES .......................................................................................................................23 
2.2 
SECONDARY OBJECTIVES...................................................................................................................23 
3 
STUDY DESIGN .............................................................................................................................24 
4 
SELECTION OF PATIENTS...........................................................................................................24 
4.1 
SAMPLE SIZE......................................................................................................................................24 
4.2 
INCLUSION CRITERIA .........................................................................................................................24 
4.3 
EXCLUSION CRITERIA........................................................................................................................26 
4.4 
REASONS OFF TREATMENT................................................................................................................27 
4.5 
REASONS OFF STUDY ........................................................................................................................28 
5 
CONCOMITANT THERAPY ...........................................................................................................29 
5.1 
DRUG-DRUG INTERACTIONS ..............................................................................................................29 
5.1.1 
Irinotecan........................................................................................................................................... 29 
5.1.2 
Carboplatin........................................................................................................................................ 30 
5.1.3 
Erbitux............................................................................................................................................... 30 
6 
THERAPEUTIC AGENTS...............................................................................................................30 
6.1 
IRINOTECAN (CAMPTOSAR®, IRINOTECAN HCL, CPT-11 PI 5/02).........................................................30 
6.1.1 
Formulation ....................................................................................................................................... 30 
6.1.2 
Storage and Stability.......................................................................................................................... 31 
6.1.3 
Preparation and Administration......................................................................................................... 31 
6.1.4 
Pharmacokinetics............................................................................................................................... 31 
6.1.5 
Adverse Effects ................................................................................................................................. 32 
6.2 
CARBOPLATIN (PARAPLATIN® OR EQUIVALENT PI 6/2001).....................................................................34 
6.2.1 
Formulation ....................................................................................................................................... 34 
6.2.2 
Storage and Stability.......................................................................................................................... 35 
6.2.3 
Preparation and Administration......................................................................................................... 35 
6.2.4 
Pharmacokinetics............................................................................................................................... 35 
6.2.5 
Adverse Effects ................................................................................................................................. 36 
6.3 
CETUXIMAB (ERBITUX™ PI 2/04)..........................................................................................................37 
6.3.1 
Supplier/How Supplied...................................................................................................................... 38 
6.3.2 
Packaging and Labeling..................................................................................................................... 38 
6.3.3 
Handling and Dispensing of Erbitux ................................................................................................. 38 
6.3.4 
Storage Requirement/Stability........................................................................................................... 38 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
3
6.3.5 
Preparation and Administration......................................................................................................... 38 
6.3.6 
Safety Precautions ............................................................................................................................. 39 
6.3.7 
Adverse Effects ................................................................................................................................. 40 
7 
INVESTIGATIONAL PLAN.............................................................................................................41 
7.1 
REGISTRATION PROCEDURES.............................................................................................................41 
7.2 
STUDY TREATMENT ADMINISTRATION..............................................................................................42 
7.2.1 
Premedications .................................................................................................................................. 42 
7.2.2 
Chemotherapy and Erbitux................................................................................................................ 42 
7.2.3 
Treatment Delay................................................................................................................................ 44 
7.2.4 
Dose Modification for Toxicity......................................................................................................... 45 
7.2.4.1 
Nonhematologic Toxicity ............................................................................................. 45 
7.2.4.2 
Hematologic Toxicity................................................................................................... 46 
7.3 
TOXICITY...........................................................................................................................................48 
8 
SCHEDULE OF ASSESSMENTS ..................................................................................................48 
8.1 
PRESTUDY ASSESSMENTS ..................................................................................................................49 
8.2 
ASSESSMENTS DURING TREATMENT..................................................................................................50 
8.3 
OFF TREATMENT ASSESSMENTS ........................................................................................................51 
8.4 
FOLLOW-UP ASSESSMENTS................................................................................................................51 
8.4.1 
Treatment Failure Follow-up............................................................................................................. 52 
8.4.2 
Response Follow-Up ......................................................................................................................... 52 
9 
SAFETY EVALUATIONS ...............................................................................................................53 
9.1 
ADVERSE EVENTS..............................................................................................................................53 
9.2 
LABORATORY DATA..........................................................................................................................53 
10 
EFFICACY ASSESSMENTS ..........................................................................................................53 
10.1 
DEFINITIONS ......................................................................................................................................53 
10.1.1 
Measurable Disease........................................................................................................................... 54 
10.1.2 
Nonmeasurable Disease..................................................................................................................... 54 
10.2 
TUMOR RESPONSE EVALUATION .......................................................................................................54 
10.2.1 
Evaluation of Lesions........................................................................................................................ 54 
10.2.1.1 
Target Lesions ............................................................................................................. 54 
10.2.1.2 
Non-target Lesions....................................................................................................... 54 
10.3 
RESPONSE CRITERIA..........................................................................................................................55 
10.3.1 
Evaluation of Target Lesions............................................................................................................. 55 
10.3.2 
Evaluation of Non-Target Lesions..................................................................................................... 55 
10.3.3 
Evaluation of Best Overall Response ................................................................................................ 56 
10.4 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE................................................................56 
10.5 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE...............................................................57 
10.5.1 
Confirmation ..................................................................................................................................... 57 
10.5.2 
Duration of Response ........................................................................................................................ 57 
10.5.3 
Duration of Stable Disease ................................................................................................................ 58 
10.6 
PROGRESSION-FREE SURVIVAL ..........................................................................................................58 
10.7 
TIME TO PROGRESSION ......................................................................................................................58 
10.8 
SURVIVAL..........................................................................................................................................58 
10.9 
TIME TO RESPONSE............................................................................................................................58 
11 
STATISTICAL CONSIDERATIONS ...............................................................................................59 
11.1 
PATIENT POPULATIONS......................................................................................................................59 
11.1.1 
Efficacy Analysis............................................................................................................................... 59 
11.2 
OBJECTIVES AND ENDPOINTS.............................................................................................................59 
11.3 
SAMPLE SIZE......................................................................................................................................60 
11.4 
STATISTICAL METHODS.....................................................................................................................60 
PART II – PROCEDURES........................................................................................................................61 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ...........................................................61 
12.1 
DEFINITIONS.......................................................................................................................................61 
12.1.1 
Adverse Event ................................................................................................................................... 61 
12.1.2 
Serious Adverse Event....................................................................................................................... 61 
12.1.3 
Unexpected Adverse Event................................................................................................................ 63 
12.2 
REPORTING.........................................................................................................................................63 
12.2.1 
Adverse Events.................................................................................................................................. 63 
12.2.2 
Serious Adverse Events..................................................................................................................... 63 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
4
12.2.3 
Overdose............................................................................................................................................ 64 
12.2.4 
Discontinuation of Patient ................................................................................................................. 64 
12.3 
PREGNANCY.......................................................................................................................................64 
13 
PROTOCOL AND DATA DEVELOPMENT....................................................................................65 
13.1 
ETHICS ...............................................................................................................................................65 
13.1.1 
Institutional Review Board................................................................................................................ 65 
13.1.2 
Patient Informed Consent .................................................................................................................. 66 
13.1.3 
Confidentiality of Records................................................................................................................. 66 
13.2 
STUDY RECORDS ................................................................................................................................66 
13.2.1 
Documentation .................................................................................................................................. 66 
13.2.2 
Electronic Case Report Form Procedures.......................................................................................... 67 
13.3 
MONITORING/SITE VISITS....................................................................................................................67 
13.4 
MODIFICATION OF PROTOCOL.............................................................................................................68 
APPENDIX I 
ECOG PERFORMANCE STATUS SCALE ...........................................................72 
APPENDIX II 
STAGING................................................................................................................73 
APPENDIX III 
CALCULATIONS....................................................................................................74 
APPENDIX IV 
SEQUENCE OF DISEASE STATUS WITH CORRESPONDING BEST 
RESPONSE............................................................................................................75 
APPENDIX V 
SCHEDULE OF ASSESSMENTS..........................................................................76 
APPENDIX VI 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE), VERSION 
3.0 ...........................................................................................................................77 
APPENDIX VII 
PATHOLOGY SUBMISSION PROCEDURE .........................................................78 
 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
5
In-Text Tables 
Table 1. 
Objective Response Rates per Independent Review..................................................18 
Table 2. 
Time to Progression per Independent Review...........................................................18 
Table 3. 
Incidence of Adverse Events (≥10%) in Patients with Advanced Colorectal 
Carcinoma..................................................................................................................21 
Table 4. 
Summary of Mean (±SD) CPT-11 and SN38 Pharmacokinetic Parameters in 
Patients with Solid Tumors........................................................................................32 
Table 5. 
Adverse Events Attributed to CPT-11 (Irinotecan) in Patients with Metastatic 
Colorectal Cancer.......................................................................................................33 
Table 6. 
Adverse Experiences in Ovarian Cancer Patients Treated with Carboplatin ............37 
Table 7. 
Erbitux Dose Levels...................................................................................................43 
Table 8. 
Treatment Schema .....................................................................................................44 
Table 9. 
Dose Reductions for Nonhematological Toxicities...................................................45 
Table 10. Dose Reductions for Hematological Toxicity Day 8 of Each Cycle .........................46 
Table 11. Erbitux Dose Modification Guidelines – Dermatologic Toxicity..............................48 
Table 12. Evaluation of Best Overall Response ........................................................................56 
 
In-Text Figures  
Figure 1. Conversion of irinotecan to SN-38 by de-esterification4...........................................12 
Figure 2. Schematic representation of cellular sensitivity and resistance to 
topoisomerase inhibitors 5..........................................................................................13 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
6
ABBREVIATIONS 
Abbreviation 
Term 
5-FU 
fluorouracil 
ALT 
alanine transaminase (also referred to as SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (also referred to as SGOT) 
AUC 
area under curve 
BMS 
Bristol-Myers Squibb 
BUN 
blood urea nitrogen 
Cmax 
maximum mean serum concentration 
CO2 
total carbon dioxide  
CBC 
complete blood count 
CR 
complete response 
ClCr 
creatinine clearance 
(CR+PR) 
objective responses 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG PS 
Eastern Cooperative Oncology Group Performance Score 
eCRF 
electronic case report form 
EGF 
Epidermal growth factor 
EGFR 
epidermal growth factor receptor 
IRC 
independent review committee 
ILD 
Interstitial lung disease 
IRB 
Institutional Review Board 
MBC 
metastatic breast cancer 
NCI 
National Cancer Institute 
ICb 
irinotecan and carboplatin  
PD 
progressive disease 
Pfizer 
Pfizer, Inc. 
PFS 
progression-free survival 
PR 
partial response 
SD 
stable disease 
SI 
Study Investigator 
TGF-α 
transforming growth factor-alpha 
TTP 
time to progression 
ULN 
upper limits of normal 
USON 
US Oncology, Inc. 
USOR 
US Oncology Research, Inc. 
WNL 
within normal limits 
 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
7
SYNOPSIS 
Summary: 
Irinotecan and carboplatin (ICb) is a synergistic antineoplastic combination in several cancers. 
Weekly irinotecan is highly active in MBC.27 Epidermal growth factor receptor (EGFR) inhibition 
enhances antitumor activity of both irinotecan and cisplatin in breast cancer preclinical models.28, 
29 We hypothesize that the addition of Erbitux to ICb will increase the overall response rate of the 
ICb combination and will prolong the median time to progression for patients with metastatic 
breast cancer. 
Objectives: 
Primary objectives: 
• 
To determine the objective response rates produced by irinotecan and carboplatin therapy with 
or without Erbitux 
Secondary objectives: 
• 
To calculate the duration of response and stable disease 
• 
To determine the median progression-free survival (PFS) and time to progression (TTP – only 
for those who progress)  
• 
To determine the median overall survival (OS)  
• 
To determine toxicities for individuals with metastatic breast cancer treated with these study 
regimens 
• 
To determine EGFR expression for individuals with metastatic breast cancer enrolled on this 
study 
Number of patients: A total of 154 patients with MBC will be enrolled in this trial. Patients will 
be randomized 1:1 to either ICb + Erbitux or ICb alone followed by Erbitux at progression. One 
third of the patients in each treatment arm will have hormone receptor negative (ER- and PR-) and 
HER2 negative (-) breast cancer (triple negative). 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
8
Inclusion Criteria: 
Note: Please see Section 8.1 for the necessary “Prestudy Assessments”. 
Male and female patients will be eligible for inclusion in this study if they meet all of the 
following criteria: 
1. Has cytologically or pathologically confirmed breast cancer with documented HER2+ 
(positive) (3+ by IHC or FISH+) or HER2- (negative) disease. ER, PR, and HER2 status must 
be documented in the electronic Case Report Form (eCRF). 
Note: Patients whose breast cancers are HER2 (2+) by IHC must undergo FISH testing to 
confirm HER2+ (positive) status.  
2. Has clinically confirmed Stage IV metastatic breast cancer (MBC) 
3. Has undergone prior Herceptin therapy if breast cancer is HER2+ (positive) 
Note: Ascites, pleural effusion, and bone metastases are not considered measurable. 
4. Has measurable MBC as defined by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Criteria in Section 10. 
5. Has had up to 1 prior chemotherapy regimens for metastatic disease. Previously untreated 
disease is permitted. 
6. Has had no prior treatment with irinotecan, carboplatin, or cisplatin 
7. Has an ECOG Performance Status (PS) 0-2 (Appendix I) 
8. Is ≥18 years of age 
9. Has laboratory values of:  
 
10. Any prior radiation therapy has been completed >2 weeks prior to the start of study treatment. 
Note: Previously irradiated lesions will not be evaluable; however, these patients will still be 
eligible. Patients must have at least 1 measurable lesion at baseline. 
11. Has had a negative serum pregnancy test within 7 days prior to registration (female patients of 
childbearing potential). A pregnancy test is also required within 7 days of Dose 1. 
12. If fertile, patient (male or female) has agreed to use an acceptable method of birth control to 
avoid pregnancy for the duration of the study and for a period of 6 months thereafter 
13. Has signed a Patient Informed Consent Form  
14. Has signed a Patient Authorization Form (HIPAA) 
15. Has paraffin-embedded breast cancer tissue (either paraffin blocks or 20 unstained slides) 
available for analysis of EGFR, cytokeratin, and other biological markers. These samples will 
be sent to the Molecular Profiling Institute (MPI; see Appendix VII).  
Note: Availability of samples should be confirmed prior to randomization (at latest, prior to first 
dose). 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
9
Exclusion Criteria: 
Patients will be excluded from this study if they meet any of the following criteria:  
1. Has Stage I-III breast cancer or nonmeasurable metastatic breast cancer, or any disease other 
than that described in inclusion criterion #1 
2. Has received prior treatment with irinotecan, carboplatin, or cisplatin  
3. Is receiving any concurrent chemotherapy not indicated in the study protocol or any other 
investigational agent(s) 
4. Has received prior therapy, which specifically and directly targets the EGFR pathway. Prior 
Herceptin is required for HER2+ patients. 
5. Has had prior severe infusion reaction to a monoclonal antibody 
6. Has received organ allograft(s) other than corneal, bone, or skin 
7. Has clinically significant uncontrolled cardiac disease (eg, congestive heart failure, 
symptomatic coronary artery disease or cardiac arrhythmias not well-controlled with 
medication) or has had a myocardial infarction <12 months 
8. Has ongoing peripheral neuropathy >Grade 1 
9. Has evidence of symptomatic or untreated central nervous system (CNS) metastases (unless 
CNS metastases have been irradiated). Chronic steroid treatment for the treatment of CNS 
metastases must have been discontinued for >4 weeks prior to study enrollment. 
10. Has any other significant comorbidity that, in the opinion of the clinical Investigator, might 
compromise any aspect of the study 
11. Has active or uncontrolled infection 
12. Has acute hepatitis or is known to be HIV positive 
13. Has a history of other malignancy within the last 5 years which could affect the diagnosis or 
assessment of MBC, with the exception of carcinoma of the cervix in situ, carcinoma of the 
bladder in situ, and basal cell carcinoma 
14. Has previously completed a chemotherapy regimen within 3 weeks prior to the start of study 
treatment, or has related toxicities unresolved prior to the start of study treatment. 
Note: If patient was receiving prior weekly or daily chemotherapy, he/she may begin study 
therapy 2 weeks after stopping prior therapy provided all toxicities have resolved; peripheral 
neuropathy must be <Grade 1 as per exclusion criterion #8 above. 
15. Has had major surgery within 3 weeks from the start of study treatment, without complete 
recovery 
16. Has participated in any investigational drug study within 4 weeks preceding the start of study 
treatment 
17. Has received a concurrent immunotherapy or hormonal anticancer agent within 2 weeks prior 
to the start of the study treatment 
18. Is receiving a tyrosine kinase inhibitor (ie, Iressa™) 
19. Has had any prior stem cell or bone marrow transplant for any prior hematologic malignancy  
20. Is pregnant or lactating 
21. Is unable to comply with requirements of study 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
10
Medication 
and Doses: 
  vvv 
 
Note: that the first dose (Day 1 of Cycle 1 only) is 400 mg/m2. All other doses 
 
 
Note: The first dose (Day 1 of Cycle 1 only) is 400 mg/m2. All other doses of 
Erbitux are 250 mg/m2. Patients whose disease progresses on ICb alone (Arm 1) or 
whose disease progresses after an ICb drug holiday, provided that they have not 
had any intervening nonprotocol therapy, will cross over to receive single-agent 
weekly Erbitux at the same dosage as described in Arm 2 of the study until disease 
progression. 
Duration: 
Subsequent cycles will be initiated every 3 weeks, and will be continued until a 
patient shows evidence of disease progression or intolerable toxicity. Patients will 
participate in this study until disease progression. 
Efficacy Assessments: 
• 
Response rates 
• 
Duration of response and stable disease 
• 
Median progression-free survival 
• 
Time to progression 
• 
Median overall survival 
Safety Assessments: 
• 
Toxicities (graded as per NCI CTCAE v3) 
• 
EGFR expression of tumor tissue 
 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
11
PART I – CLINICAL TRIAL PROTOCOL 
1 INTRODUCTION 
1.2 
BACKGROUND ON BREAST CANCER 
Breast cancer is the most common type of noncutaneous cancer among women in the 
United States, and it is estimated that in 2005, about 211,240 new cases of invasive breast 
cancer will be diagnosed.1 Moreover, breast cancer is second only to lung cancer in 
cancer deaths in women, and by the end of this year, over 40,000 women will lose their 
lives to this disease.1 The risk of breast cancer increases gradually with age. Most breast 
cancers occur in women over age 50, and after age 60, the risk is especially high (median 
age of patients with breast cancer is between 60-65 years). Despite successful initial 
treatment, breast cancer will recur in approximately 50% of patients. The 5-year relative 
survival rate for localized breast cancer (cancer that has not spread to lymph nodes or 
other locations outside the breast) has increased from 80% in the 1950s to 98% today. In 
cases of metastatic breast cancer (where the cancer has spread regionally), however, the 
5-year survival rate is 80%, and for women with distant metastases, the rate is 26%.1 
Breast cancer is staged according to the American Joint Committee on Cancer Breast 
TNM Staging Tool (Appendix II). 
1.1.1 
Chemotherapy in Breast Cancer 
Adjuvant chemotherapy has been shown to substantially improve the long-term, 
relapse-free survival, and overall survival in both premenopausal and postmenopausal 
women <70 years of age with both node-positive and node-negative disease.2 
Furthermore, the use of polychemotherapy (>2 agents) is superior to single agents. Four 
to 6 cycles of therapy have been shown to provide the most robust results as additional 
cycles of therapy usually magnify the toxicity profile without any evident benefit. In the 
1970s, anthracyclines (ie, doxorubicin and epirubicin) were on the forefront and were 
used as adjuvant polychemotherapy for breast cancer. Research showed that threshold 
dose effects for 2 of the most active chemotherapeutic agents, doxorubicin (A) and 
cyclophosphamide (C), which are frequently given together (AC), appeared to result in a 
small, but statistically significant improvement versus non-anthracycline containing 
compounds..2 In the 1980s, the platinum agents gained popularity as carboplatin and 
cisplatin showed promising improvements in cancer treatment. In the 1990s, the taxanes 
(docetaxel and paclitaxel) were found to be active agents in the treatment of metastatic 
breast cancer (MBC). Despite the regular use of a number of cytotoxic drugs for the 
treatment of MBC and polychemotherapy regimens derived from them, the median 
survival for patients with MBC has not been dramatically improved over the last 
2 decades. 
 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
12
1.2 
BACKGROUND ON IRINOTECAN 
Note: Since Camptosar goes off patent in 2007 (during the course of this study) 
the generic drug (irinotecan) is used throughout the document. 
Irinotecan is approved for the treatment of patients with metastatic carcinoma of the 
colon or rectum whose disease has recurred or progressed following 5-FU-based therapy. 
The approval was based on 3 studies; the studies showed an overall response rate of 
12.8% (95% CI: 9.1%-16.6%; 0.7% CR, 12.2% PR) in 304 patients.3 Among the 
193 patients treated at the 125 mg/m2 starting dose, the overall response rate was 15.0% 
(95% CI: 10.0%, 20.1%[2 CR, 27 PR]). The median duration of response was 6 months 
(range, 2.6-15.1 months). The median duration of response for patients beginning therapy 
at 125 mg/m2 was 5.8 months (range, 2.6-15.1). Dose limiting toxicities included severe 
delayed diarrhea and myelosuppression.  
Irinotecan itself is a relatively inactive prodrug; however, once it is converted by 
carboxylesterases to SN-38 (Figure 1), it becomes 2- to 2000-fold more potent as an 
inhibitor of the nuclear enzyme topoisomerases I. 
 
Figure 1. 
Conversion of irinotecan to SN-38 by de-esterification4 
Irinotecan and its active metabolite SN-38 bind to the topoisomerase/DNA complex. 
Since topoisomerase I complexes with DNA only during DNA synthesis, the cytotoxic 
action of the irinotecan metabolite likely takes place during S-phase. The formation of a 
topoisomerase I/camptothecin/DNA–cleavable complex results in cell injury or death. 
Cleavable complexes affect DNA damage through interference with DNA metabolism 
and damage to the DNA replication fork. After exposure to irinotecan hydrochloride and 
SN-38 during DNA replication, DNA contains double-strand breaks in the replication 
forks, unlike the typical single-strand breaks associated with topoisomerase I. It is 
postulated that topoisomerase I inhibitors kill cells by stabilizing topoisomerase I DNA 
breaks, causing irreversible double-strand breaks through interference with the process of 
replication.  
Factors that help determine antitumor cytotoxic effects are outlined in Figure 2. Cells 
with higher levels of topoisomerase are likely more sensitive to topoisomerase inhibition. 
Resistant cells generally have low levels of topoisomerase and fewer cleavable 
complexes. Because irinotecan has a unique mechanism of action, clinical response can 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
13
be achieved with single-agent therapy in patients who have developed resistance to 
5-FU-based regimens. 
It has been reported that human colon tumors express high levels of the 
multiple-drug-resistance 1 (MDR1) gene product, which in cultured cells may limit 
access of certain drugs to cells.5 In vitro data have demonstrated that camptothecin and its 
noncharged derivatives such as irinotecan overcome MDR1-mediated resistance.  
 
 
Figure 2. 
Schematic representation of cellular sensitivity and resistance to 
topoisomerase inhibitors 5 
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by 
carboxylesterase enzymes and occurs primarily in the liver. SN-38 subsequently 
undergoes conjugation to form a glucuronide metabolite (SN-38 glucuronide). SN-38 
glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using 2 cell 
lines in vitro. The disposition of irinotecan has not been fully elucidated in humans. 

US Oncology, Inc. 
 
04-070 
Irinotecan and carboplatin, with and without Erbitux® 
April 12, 2010 
in patients with metastatic breast cancer 
 
 
14
1.3 
BACKGROUND ON CARBOPLATIN  
Carboplatin is an analog of cisplatin. Like cisplatin, it contains a platinum atom 
surrounded in a plane by 2 ammonia groups and 2 other ligands in the cis position. The 
other 2 ligands in carboplatin are present in a ring structure rather than as 2 chloride 
atoms in cisplatin. This difference makes carboplatin more stable and has less 
nephrotoxicity, neurotoxicity, ototoxicity and emetogenesis.7,8 The exact mechanism of 
action of carboplatin is not known. Carboplatin undergoes intracellular activation to form 
reactive platinum complexes, which are believed to inhibit DNA synthesis by forming 
interstrand and intrastrand cross-linking of DNA molecules. Carboplatin is a 
radiation-sensitizing agent.9,10 It is cell cycle-phase nonspecific.8 
1.3.1 
Carboplatin in the Treatment of Metastatic Breast Cancer 
In 1991, Kolaric and colleagues conducted a Phase II study to determine if carboplatin 
had any activity against untreated metastatic breast cancer.11 A total of 20 patients were 
entered in the study and all were evaluable. Carboplatin was administered IV at a dose of 
400 mg/m2 on day 1, with a 3-week rest period. Carboplatin activity was observed in 
4 patients [2 complete remissions (CRs) and 2 partial responses (PRs), for a response rate 
of 20% (4/20). Remission lasted 2-10 months (mean, 4 months). Toxicity was moderate, 
producing no drug-related deaths.11 These results were later confirmed by a similar study 
conducted by Martin et al. on patients with advanced metastatic breast cancer. In this 
study 400 mg/m2 of carboplatin were administered IV every 4 weeks. In this study, 
patients without prior chemotherapy achieved a 35% response rate. Interestingly, patients 
with prior exposure to chemotherapy did not respond to carboplatin therapy.12 A current 
study by Robert et al. also shows the benefits of carboplatin combination therapy women 
with HER2 overexpressing MBC. In this study 196 women with HER2 overexpressing 
MBC received either trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter), 
with paclitaxel (175 mg/m2), and carboplatin (AUC 6) every 3 weeks followed by weekly 
trastuzumab, or 6 cycles of trastuzumab (4 mg/kg loading dose, 2 mg/kg) weekly 
thereafter with paclitaxel (175 mg/m2) every 3 weeks. Overall response was 52% for the 
trastuzumab + paclitaxel + carboplatin (TPC) arm of the study versus 36% for the 
trastuzumab + paclitaxel (TP) arm. Median time to progression was 10.7 months for TPC 
and 7.0 months for TP. Both regimens were well tolerated, though 
Grade 3 thrombocytopenia and Grade 4 neutropenia occurred more frequently with 
TPC.13 
1.4 
BACKGROUND ON IRINOTECAN AND CARBOPLATIN  
Currently irinotecan and carboplatin are not used in combination for metastatic breast 
cancer. The combination, however, is commonly used to treat NSCLC. Wild et al 
reported their results for a Phase I trial of irinotecan and carboplatin in NSCLC.13a In 
their study 74 subjects were treated with escalating doses of irinotecan and carboplatin. 
The most common toxicity observed was neutropenia and subjects had a 40% RR to the 
therapy. They determined the population minimum tolerated dose (pMTD) for 
irinotecan/carboplatin to be 200 mg/m2/ AUC=4 for chemo-naïve patients, and 
150 mg/m2/AUC=5 for individuals previously treated with chemotherapy. Fukuda et al 

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expanded on these findings in 2004 in their Phase II study of irinotecan and carboplatin 
to treat NSCLC. 14 Their study treated 61 patients with Stage IV disease. Subjects were 
dosed with irinotecan 50 mg/m2 (Days 1, 8, and 15) and carboplatin AUC=5 on Day 1 of 
each 4-week cycle with an AUC of 5 mg min/mL. Of the 61 subjects, 59 were evaluable 
for toxicity. The most common Grade 3-4 toxicity was neutropenia. Median survival was 
10 months. Twenty subjects had a partial response and 26 had stable disease. The overall 
response rate was 34%.  
While the combination of irinotecan with other therapeutic agents has not been studied in 
the treatment of metastatic breast cancer, there is mounting evidence that irinotecan 
would serve as an effective agent to treat MBC. Irinotecan has been used to treat 
advanced recurrent breast cancer. In 2003 Okubo et al. reported on the use of irinotecan 
on 35 patients with advanced or recurrent breast cancer.14a In this study, patients received 
a weekly dose of irinotecan of 40-160 mg/body. An objective response rate of 6% and a 
clinical benefit rate of 23% were observed.  
Perez et al conducted a Phase II study comparing 2 different irinotecan schedules for 
patients with MBC resistant to anthracyclines or taxanes.14b In this study, 52 patients with 
MBC were treated with 6-week cycles comprising 100 mg/m2 weekly for 4 weeks, then a 
2-week rest; 51 patients were treated with 240 mg/m2 every 3 weeks. Patients receiving 
weekly irinotecan had an objective response of 23%. Patients receiving therapy every 
3 weeks had an objective response of 14%. Median response of duration for weekly 
therapy was 4.9 months versus 4.2 months for the every-3-week schedule. Median overall 
survival was 9.7 months with weekly therapy versus 8.6 months for every-3-week 
therapy.  
1.5 
BACKGROUND ON ERBITUX (CETUXIMAB) 
The epidermal growth factor receptor (EGFR) is a member of the erb B receptor tyrosine 
kinase family that includes erb B-2, erb B-3, and erb B-4.15 It consists of an extracellular 
ligand-binding domain, a transmembrane region that anchors the receptor to the plasma 
membrane, and a cytoplasmic region containing a tyrosine kinase domain. The known 
natural ligands of EGFR include epidermal growth factor (EGF) and transforming growth 
factor-alpha (TGF-α), which both activate the receptor by binding to the extracellular 
domain and inducing the formation of receptor homodimers or heterodimers, followed by 
internalization of the receptor/ligand complex and auto-phosphorylation. It is now 
accepted that the EGFR signal transduction network plays an important role in multiple 
tumorigenic processes, including cell cycle progression, angiogenesis, and metastasis, as 
well as protection from apoptosis.15,16 In this signal network, erb B-2 is the major partner 
of EGFR because activated heterodimer complexes containing erb B-2 are more stable at 
the cell surface than complexes containing other EGFR family members.17,18 In addition 
erb B-2 can decrease the rate of ligand dissociation from the cognate receptor EGFR.19  
The effects of EGFR blockade on cell cycle progression have been investigated in several 
human cell types, including DiFi colon adenocarcinoma cells, non-transformed breast 
epithelial MCF10A cells, A431 squamous epithelial carcinoma cells, and DU145 
prostatic cancer cells. These studies suggest that blocking EGFR with monoclonal 

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antibodies such as cetuximab leads to cell cycle arrest in G1, which is accompanied by a 
decrease in cyclin dependent kinase (CDK) 2 activity, and an increase in the expression 
of CDK inhibitor p27kip1. 20,21 In addition to inducing G1-phase arrest, EGFR blockade 
was also shown to lead to cell death via apoptosis in DiFi colon adenocarcinoma cells.22 
Cetuximab binds specifically to the epidermal growth factor receptor (EGFR, HER1, 
c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of EGF 
and other ligands, such as TGF-α.23 Binding of cetuximab to the EGFR blocks 
phosphorylation and activation of receptor-associated kinases, resulting in inhibition of 
cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular 
endothelial growth factor production. The EGFR is a transmembrane glycoprotein that is 
a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1), 
HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal 
epithelial tissues, including the skin and hair follicle. Overexpression of EGFR is also 
detected in many human cancers including those of the colon and rectum.  
In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth 
and survival of tumor cells that overexpress the EGFR. No antitumor effects of 
cetuximab were observed in human tumor xenografts lacking EGFR expression. The 
addition of cetuximab to irinotecan or irinotecan plus 5-fluorouracil in animal studies 
resulted in an increase in antitumor effects compared to chemotherapy alone. 
1.5.1 
Human Pharmacokinetics 
Cetuximab administered as monotherapy or in combination with concomitant 
chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics.24 The area under the 
concentration time curve (AUC) increased in a greater than dose proportional manner as 
the dose increased from 20 to 400 mg/m2. Cetuximab clearance (CL) decreased from  
0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses 
>200 mg/m2, it appeared to plateau. The volume of distribution (Vd) for cetuximab 
appeared to be independent of dose and approximated the vascular space of 2-3 L/m2.  
Following a 2-hour infusion of 400 mg/m2 of cetuximab, the maximum mean serum 
concentration (Cmax) was 184 μg/mL (range, 92-327 μg/mL) and the mean elimination 
half-life was 97 hours (range, 41-213 hours). A 1-hour infusion of 250 mg/m2 produced a 
mean Cmax of 140 μg/mL (range, 120-170 μg/mL). Following the recommended dose 
regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), cetuximab concentrations 
reached steady-state levels by the third weekly infusion with mean peak and trough 
concentrations across studies ranging from 168 to 235 and 41 to 85 μg/mL, respectively. 
The mean half-life was 114 hours (range, 75-188 hours). 
1.5.2 
Immunogenicity 
As with all therapeutic proteins, there is potential for immunogenicity. Potential 
immunogenic responses to cetuximab were assessed using either a double antigen 
radiometric assay or an enzyme-linked immunosorbant assay. Due to limitations in assay 
performance and sampling timing, the incidence of antibody development in patients 

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receiving cetuximab has not been adequately determined. The incidence of antibodies to 
cetuximab was measured by collecting and analyzing serum prestudy, prior to selected 
infusions and during treatment follow-up. Patients were considered evaluable if they had 
a negative pretreatment sample and a post-treatment sample. Non-neutralizing 
anticetuximab antibodies were detected in 5% (28 of 530) of evaluable patients.24 In 
patients positive for anticetuximab antibody, the median time to onset was 44 days 
(range, 8-281 days). Although the number of seropositive patients is limited, there does 
not appear to be any relationship between the appearance of antibodies to cetuximab and 
the safety or antitumor activity of the molecule. 
The observed incidence of anticetuximab antibody responses may be influenced by the 
low sensitivity of available assays, inadequate to reliably detect lower antibody titers. 
Other factors, which might influence the incidence of anticetuximab antibody response, 
include sample handling, timing of sample collection, concomitant medications, and 
underlying disease. For these reasons, comparison of the incidence of antibodies to 
cetuximab with the incidence of antibodies to other products may be misleading. 
1.5.3 
Clinical Studies of Cetuximab in Colorectal Cancer: Efficacy 
The efficacy and safety of cetuximab alone or in combination with irinotecan were 
studied in a randomized, controlled trial (329 patients) and in combination with 
irinotecan in an open-label, single-arm trial (138 patients). Cetuximab was further 
evaluated as a single agent in a third clinical trial (57 patients). Safety data from 
111 patients treated with single agent cetuximab was also evaluated. All trials studied 
patients with EGFR-expressing metastatic colorectal cancer, whose disease had 
progressed after receiving an irinotecan-containing regimen.  
1.5.3.1 Randomized, Controlled Trials 
A multicenter, randomized, controlled clinical trial was conducted in 329 patients 
randomized to receive either cetuximab plus irinotecan (218 patients) or cetuximab 
monotherapy (111 patients).24 In both arms of the study, cetuximab was administered as a 
400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or 
unacceptable toxicity. All patients received a 20-mg test dose on Day 1. In the cetuximab 
plus irinotecan arm, irinotecan was added to cetuximab using the same dose and schedule 
for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 
350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly times 
4 doses every 6 weeks. An Independent Radiographic Review Committee (IRC), blinded 
to the treatment arms, assessed both the progression on prior irinotecan and the response 
to protocol treatment for all patients. 
Of the 329 randomized patients, 206 (63%) were male. The median age was 59 years 
(range, 26-84), and the majority were Caucasian (n=323, 98%). Eighty-eight percent of 
patients had baseline Karnofsky Performance Status ≥80. Fifty-eight percent of patients 
had colon cancer and 40% rectal cancer. Approximately two-thirds (63%) of patients had 
previously failed oxaliplatin treatment. 

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The efficacy of cetuximab plus irinotecan or cetuximab monotherapy was evaluated in all 
randomized patients.  
Analyses were also conducted in 2 prespecified subpopulations: irinotecan refractory and 
irinotecan and oxaliplatin failures. The irinotecan refractory population was defined as 
randomized patients who had received at least 2 cycles of irinotecan-based chemotherapy 
prior to treatment with cetuximab, and had independent confirmation of disease 
progression within 30 days of completion of the last cycle of irinotecan-based 
chemotherapy.  
The irinotecan and oxaliplatin failure population was defined as irinotecan refractory 
patients who had previously been treated with and failed an oxaliplatin-containing 
regimen. The objective response rates (ORR) in these populations are presented in 
Table 1. 
Table 1. 
Objective Response Rates per Independent Review 
 
Cetuximab + 
Irinotecan 
Cetuximab 
Monotherapy 
Difference  
(95% CIa) 
Populations 
n 
ORR (%) 
n 
ORR (%) 
n 
ORR 
(%) 
All Patients 
218  
22.9 
111  
10.8 
12.1  
(4.1 - 20.2) 
0.007 
Irinotecan-
Oxaliplatin Failure 
80  
23.8 
44  
11.4 
12.4  
(-0.8 - 25.6) 
0.09 
Irinotecan 
Refractory 
132 
25.8 
69 
14.5 
11.3  
(0.1 - 22.4) 
0.07 
a95% confidence interval for the difference in objective response rates. 
bCochran-Mantel-Haenszel test 
The median duration of response in the overall population was 5.7 months in the 
combination arm and 4.2 months in the monotherapy arm. Compared with patients 
randomized to cetuximab alone, patients randomized to cetuximab and irinotecan 
experienced a significantly longer median time to disease progression (see Table 2). 
Table 2. 
Time to Progression per Independent Review 
Populations 
Cetuximab + 
Irinotecan 
(median) 
Cetuximab 
Monotherapy 
(median) 
Hazard Ratio 
(95% CIa) 
Log-rank 
p-value  
All Patients 
4.1 mo 
1.5 mo 
0.54 (0.42 – 0.71) 
<0.001 
Irinotecan-Oxaliplatin 
Failure 
2.9 mo 
1.5 mo 
0.48 (0.31 - 0.72) 
<0.001 
Irinotecan Refractory 
4.0 mo 
1.5 mo 
0.52 (0.37 - 0.73) 
<0.001 
aHazard ratio of cetuximab + irinotecan: cetuximab monotherapy with 95% confidence interval. 
1.5.3.2 Single-Arm Trials 
Cetuximab, in combination with irinotecan, was studied in a single-arm, multicenter, 
open-label clinical trial in 138 patients with EGFR-expressing metastatic colorectal 
cancer who had progressed following an irinotecan containing regimen.25 Patients 
received a 20-mg test dose of cetuximab on Day 1, followed by a 400-mg/m2 initial dose, 

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and 250 mg/m2 weekly until disease progression or unacceptable toxicity. Patients 
received the same dose and schedule for irinotecan as the patient had previously failed. 
Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks or 125 mg/m2 weekly 
times four doses every 6 weeks. Of 138 patients enrolled, 74 patients had documented 
progression to irinotecan as determined by an independent review committee (IRC). This 
IRC used an identical charter to the IRC, which reviewed the randomized trial. The study 
was initially reported using a different IRC and charter. The overall response rate was 
15% for the overall population and 12% for the irinotecan failure population. The median 
duration of response was 6.5 and 6.7 months, respectively.23 
Cetuximab was studied as a single agent in a multicenter, open-label, single-arm clinical 
trial in patients with EGFR-expressing metastatic colorectal cancer who progressed 
following an irinotecan-containing regimen.25 Of 57 patients enrolled, 28 patients had 
documented progression on irinotecan. The overall response rate was 9% for the all 
treated group and 14% for the irinotecan failure group. The median times to progression 
were 1.4 and 1.3 months, respectively. The median duration of response was 4.2 months 
for both groups. 
1.5.3.3 EGFR Expression and Response 
Patients enrolled in the clinical studies were required to have immunohistochemical 
evidence of positive EGFR expression. Primary tumor or tumor from a metastatic site 
was tested with the DakoCytomation EGFR pharmDx™ test kit.23 Specimens were scored 
based on the percentage of cells expressing EGFR and intensity (barely/faint, weak to 
moderate, and strong). Response rate did not correlate with either the percentage of 
positive cells or the intensity of EGFR expression. 
1.5.4 
Safety of Cetuximab in Clinical Studies 
1.5.4.1 Anticipated Adverse Events  
Except where indicated, the data described below reflect exposure to cetuximab in 
774 patients with advanced metastatic colorectal cancer. Cetuximab was studied in 
combination with irinotecan (n=354) or as monotherapy (n=420). Patients receiving 
cetuximab plus irinotecan received a median of 12 doses [with 88/354 (25%) treated for 
over 6 months], and patients receiving cetuximab monotherapy received a median of 
7 doses [with 36/420 (9%) treated for over 6 months]. The population had a median age 
of 59 years and was 59% male and 91% Caucasian. The range of dosing for patients 
receiving cetuximab plus irinotecan was 1-84 infusions, and the range of dosing for 
patients receiving cetuximab monotherapy was 1-63 infusions. 
The most serious adverse reactions associated with cetuximab were:  
• Infusion reaction (3%) 
• Dermatologic toxicity (1%) 
• Interstitial lung disease (0.4%) 
• Fever (5%) 

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• Sepsis (3%) 
• Kidney failure (2%) 
• Pulmonary embolus (1%) 
• Dehydration (5%) in patients receiving cetuximab plus irinotecan, 2% in patients 
receiving cetuximab monotherapy 
• Diarrhea (6%) in patients receiving cetuximab plus irinotecan, 0% in patients 
receiving cetuximab monotherapy 
Thirty-seven patients (10%) receiving cetuximab plus irinotecan and 17 patients (4%) 
receiving cetuximab monotherapy discontinued treatment primarily because of adverse 
events.  
The most common adverse events seen in 354 patients receiving cetuximab plus 
irinotecan were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), nausea 
(55%), abdominal pain (45%), and vomiting (41%).  
The most common adverse events seen in 420 patients receiving cetuximab monotherapy 
were acneform rash (90%); asthenia/malaise (48%); nausea (29%); fever (27%); 
constipation, abdominal pain, and headache (26% each), and diarrhea (25%).  
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in practice. The 
adverse reaction information from clinical trials does, however, provide a basis for 
identifying the adverse events that appear to be related to drug use and for approximating 
rates. 
Data in patients with advanced colorectal carcinoma in Table 3 are based on the 
experience of 354 patients treated with cetuximab plus irinotecan and 420 patients treated 
with cetuximab monotherapy. 

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Table 3. 
Incidence of Adverse Events (≥10%) in Patients with Advanced Colorectal 
Carcinoma 
 
Cetuximab plus Irinotecan  
(n=354) 
Cetuximab Monotherapy 
(n=420) 
Grades 1 - 4  
Grades 3 and 4 
Grades 1 - 4  
Grades 3 and 4 
Body System  
Preferred Term1 
% of Patients 
Body as a Whole 
 
 
 
 
Asthenia/malaise2 
73 
16 
48 
10 
Abdominal pain 
45 
8 
26 
9 
Fever3 
34 
4 
27 
<1 
Pain 
23 
6 
17 
5 
Infusion reaction4 
19 
3 
21 
2 
Infection 
16 
1 
14 
1 
Back pain 
16 
3 
10 
2 
Headache 
14 
2 
26 
2 
Digestive 
 
 
 
 
Diarrhea 
72 
22 
25 
2 
Nausea 
55 
6 
29 
2 
Vomiting 
41 
7 
25 
3 
Anorexia 
36 
4 
23 
2 
Constipation 
30 
2 
26 
2 
Stomatitis 
26 
2 
10 
<1 
Dyspepsia 
14 
0 
6 
0 
Hematic/Lymphatic 
 
 
 
 
Leukopenia 
25 
17 
<1 
0 
Anemia 
16 
5 
9 
3 
Metabolic/Nutritional 
 
 
 
 
Weight loss 
21 
0 
7 
1 
Peripheral edema 
16 
1 
10 
1 
Dehydration 
15 
6 
10 
3 
Nervous 
 
 
 
 
Insomnia 
12 
0 
10 
<1 
Depression  
10 
0 
7 
0 
Respiratory 
 
 
 
 
Dyspnea3 
23 
2 
17 
7 
Cough increased 
20 
0 
11 
1 
Skin/Appendages 
 
 
 
 
Acneform rash5 
88 
14 
90 
8 
Alopecia 
21 
0 
4 
0 
Skin disorder 
15 
1 
4 
0 
Nail disorder 
12 
<1 
16 
<1 
Pruritus  
10 
1 
11 
<1 
Conjunctivitis 
14 
1 
7 
<1 
1 Adverse events that occurred (toxicity Grades 1 through 4) in ≥10% of patients with refractory colorectal carcinoma 
treated with cetuximab plus irinotecan or in ≥10% of patients with refractory colorectal carcinoma treated with cetuximab 
monotherapy. 
2 Asthenia/malaise is defined as any event described as “asthenia”, “malaise”, or “somnolence”. 
3 Includes cases reported as infusion reaction. 
4 Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or 
“anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid 
reaction”, “fever”, “chills”, “chills and fever” or “dyspnea”. 
5 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “postural rash”, “dry skin”, or 
“exfoliative dermatitis”. 

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1.5.4.2 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 19% of patients 
receiving cetuximab monotherapy.  
A 20-mg test dose of cetuximab was administered intravenously over 10 minutes prior to 
the initial dose to all patients in earlier studies. The test dose did not reliably identify 
patients at risk for severe allergic reactions. 
Severe infusion reactions occurred with the administration of cetuximab in approximately 
3% of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe 
infusion reactions were associated with the first infusion of cetuximab despite the use of 
prophylactic antihistamines. These reactions were characterized by the rapid onset of 
airway obstruction (bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. 
1.5.4.3 Pulmonary Toxicity 
Interstitial lung disease (ILD) was reported in 3 of 774 (<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. 
1.5.4.4 Dermatologic Toxicity 
In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 
4 times the weekly human exposure (based on total body surface area), resulted in 
dermatologic findings, including inflammation at the injection site and desquamation of 
the external integument.23 At the highest dose level, the epithelial mucosa of the nasal 
passage, esophagus, and tongue were similarly affected, and degenerative changes in the 
renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of 
the animals at the highest dose level beginning after approximately 13 weeks of 
treatment. 
In clinical studies of cetuximab, dermatologic toxicities, including acneform rash, skin 
drying and fissuring, and inflammatory and infectious sequelae (eg, blepharitis, cheilitis, 
cellulitis, cyst) were reported. In patients with advanced colorectal cancer, acneform rash 
was reported in 89% (686/774) of all treated patients, and was severe (Grade 3 or 4) in 
11% (84/774) of these patients. Subsequent to the development of severe dermatologic 

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toxicities, complications including S. aureus sepsis and abscesses requiring incision and 
drainage were reported.  
Non-suppurative acneform 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% (8% Grade 3) of patients receiving cetuximab monotherapy. 
Acneform 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 (eg, blepharitis, cellulitis, cyst). 
Two cases of S. aureus sepsis were reported. The onset of acneform rash was generally 
within the first 2 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 (0.4% 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. 
1.6 
RATIONALE 
Irinotecan and carboplatin (ICb) is a synergistic antineoplastic combination in several 
cancers. Weekly irinotecan is highly active in MBC.27 Epidermal growth factor receptor 
(EGFR) inhibition enhances antitumor activity of both irinotecan and cisplatin in breast 
cancer preclinical models.28, 29 We hypothesize that the addition of Erbitux to ICb will 
increase the overall response rate of the ICb combination and will prolong the median 
time to progression for patients with metastatic breast cancer.  
2 TRIAL OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
• To determine the objective response rates produced by irinotecan and carboplatin 
therapy with or without Erbitux 
2.2 
SECONDARY OBJECTIVES 
• To calculate the duration of response and stable disease 
• To determine the median progression-free survival (PFS) and time to progression 
(TTP – only for those who progress)  
• To determine the median overall survival (OS)  
• To determine toxicities for individuals with metastatic breast cancer treated with 
these study regimens 

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• To determine EGFR expression for individuals with metastatic breast cancer enrolled 
on this study 
3 STUDY DESIGN 
This is a Phase II, noncomparative, randomized study. Patients will receive either 
irinotecan 90 mg/m2 and carboplatin AUC=2.0 on Days 1 and 8 of each 21-day cycle 
(Arm 1, ICb) or irinotecan 90mg/m2, carboplatin AUC=2.0 on Days 1 and 8 of each 21-
day cycle plus Erbitux 400 mg/m2 Week 1 and then 250 mg/m2 weekly thereafter, (Arm 
2, ICb+Erbitux). Cycles will be repeated every 3 weeks. Therapy will continue until 
disease progression or unacceptable toxicity.  
Note: Crossover is one way; only Arm 1 crosses over. 
Patients who progress on Arm 1 will cross over to receive Erbitux alone. Patients on 
Arm 1 who stopped taking ICb for toxicity and who have not received intervening 
nonprotocol therapy should also cross over to receive Erbitux alone at the time of disease 
progression. Single-agent Erbitux will be given at a loading dose of 400 mg/m2 for 
Week 1 followed by 250 mg/m2 weekly thereafter, until the further development of PD 
(patient’s PD on ICb is baseline disease on Erbitux as single agent; additional criteria for 
PD must be met to qualify as PD on single-agent Erbitux) or unacceptable toxicity. 
Note: Arm 1 patients on ICb drug holiday who are not receiving intervening nonprotocol 
therapy should receive all regularly scheduled on-study assessments and tests at each 
cycle, including laboratory tests. 
Patients will be assessed for response, progression, and survival. In addition, the toxicity 
and safety profiles of the 2 treatment arms will be evaluated. 
4 SELECTION OF PATIENTS 
4.1 
SAMPLE SIZE 
A total of 154 patients with MBC will be enrolled in this trial. Patients will be 
randomized 1:1 to either ICb + Erbitux or ICb alone followed by Erbitux at progression. 
One-third of the patients (24 patients) in each treatment arm will have hormone receptor 
negative (ER- and PR-) and HER2 negative (-) breast cancer (triple negative). 
4.2 
INCLUSION CRITERIA 
Note: Please see Section 8.1 for the necessary “Prestudy Assessments”. 
Male and female patients will be eligible for inclusion in this study if they meet all of 
the following criteria:  

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1. Has cytologically or pathologically confirmed breast cancer with documented HER2+ 
(positive) (3+ by IHC or FISH+) or HER2- (negative) disease. ER, PR, and HER2 
status must be documented in the electronic Case Report Form (eCRF). 
Note: Patients whose breast cancers are HER2 (2+) by IHC must undergo FISH testing to 
confirm HER2+ (positive) status.  
2. Has clinically confirmed Stage IV metastatic breast cancer (MBC) 
3. Has undergone prior Herceptin therapy if breast cancer is HER2+ (positive) 
4. Has measurable MBC as defined by the Response Evaluation Criteria in Solid 
Tumors (RECIST) Criteria in Section 10.  
Note: Ascites, pleural effusion, and bone metastases are not considered measurable. 
5. Has had up to 1 prior chemotherapy regimens for metastatic disease. Previously 
untreated disease is permitted. 
6. Has had no prior treatment with irinotecan, carboplatin, or cisplatin  
7. Has an ECOG Performance Status (PS) 0-2 (Appendix I) 
8. Is ≥18 years of age  
9. Has laboratory values of:  
Absolute neutrophil count (ANC) 
≥1000 x 106/L 
Hemoglobin 
≥9 g/dL 
Total bilirubin 
 
≤1.5 mg/dL 
AST and ALT 
 
≤2.5 x upper limit of normal (ULN) unless liver 
metastases present, then ≤5 x ULN allowed  
Serum creatinine 
≤2.0 mg/dL 
Platelet count 
≥75,000 x 106/L 
10. Any prior radiation therapy has been completed >2 weeks prior to the start of study 
treatment. 
Note: Previously irradiated lesions will not be evaluable; however, these patients will 
still be eligible. Patients must have at least 1 measurable lesion at baseline. 
11. Has had a negative serum pregnancy test within 7 days prior to registration (female 
patients of childbearing potential). A pregnancy test is also required within 7 days of 
Dose 1. 
12. If fertile, patient (male or female) has agreed to use an acceptable method of birth 
control to avoid pregnancy for the duration of the study and for a period of 6 months 
thereafter 
13. Has signed a Patient Informed Consent Form 

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14. Has signed a Patient Authorization Form (HIPAA) 
15. Has paraffin-embedded breast cancer tissue (either paraffin blocks or 20 unstained 
slides) available for analysis of EGFR, cytokeratin, and other biological markers. 
These samples will be sent to the Molecular Profiling Institute (MPI; see Appendix 
VII). 
Note: Availability of samples should be confirmed prior to randomization (at latest, prior 
to first dose). 
4.3 
EXCLUSION CRITERIA 
Patients will be excluded from this study if they meet any of the following criteria:  
1. Has Stage I-III breast cancer or nonmeasurable metastatic breast cancer, or any 
disease other than that described in inclusion criterion #1 
2. Has received prior treatment with irinotecan, carboplatin, or cisplatin  
3. Is receiving any concurrent chemotherapy not indicated in the study protocol or any 
other investigational agent(s) 
4. Has received prior therapy, which specifically and directly targets the EGFR 
pathway. Prior Herceptin is required for HER2+ patients. 
5. Has had prior severe infusion reaction to a monoclonal antibody 
6. Has received organ allograft(s) other than corneal, bone, or skin 
7. Has clinically significant uncontrolled cardiac disease (eg, congestive heart failure, 
symptomatic coronary artery disease or cardiac arrhythmias not well-controlled with 
medication) or has had a myocardial infarction <12 months 
8. Has ongoing peripheral neuropathy >Grade 1 
9. Has evidence of symptomatic or untreated central nervous system (CNS) metastases 
(unless CNS metastases have been irradiated). Chronic steroid treatment for the 
treatment of CNS metastases must have been discontinued for >4 weeks prior to 
study enrollment. 
10. Has any other significant comorbidity that, in the opinion of the clinical Investigator, 
might compromise any aspect of the study 
11. Has active or uncontrolled infection 
12. Has acute hepatitis or is known to be HIV positive 

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13. Has a history of other malignancy within the last 5 years which could affect the 
diagnosis or assessment of MBC, with the exception of carcinoma of the cervix in 
situ, carcinoma of the bladder in situ, and basal cell carcinoma 
14. Has previously completed a chemotherapy regimen within 3 weeks prior to the start 
of study treatment, or has related toxicities unresolved prior to the start of study 
treatment. 
Note: If patient was receiving prior weekly or daily chemotherapy, he/she may begin 
study therapy 2 weeks after stopping prior therapy provided all toxicities have resolved; 
peripheral neuropathy must be <Grade 1 as per exclusion criterion #8 above. 
15. Has had major surgery within 3 weeks from the start of study treatment, without 
complete recovery 
16. Has participated in any investigational drug study within 4 weeks preceding the start 
of study treatment 
17. Has received a concurrent immunotherapy or hormonal anticancer agent within 
2 weeks prior to the start of the study treatment 
18. Is receiving a tyrosine kinase inhibitor (ie, Iressa™) 
19. Has had any prior stem cell or bone marrow transplant for any prior hematologic 
malignancy  
20. Is pregnant or lactating 
21. Is unable to comply with requirements of study 
4.4 
REASONS OFF TREATMENT 
Patients will be taken off treatment if any of the following occur: off treatment 
assessments (Section 8.3) should be completed within 7 days following the last dose of 
study drug.  
1. Disease progression Arm 2 only (follow as per Section 8.4.1). Arm 1 patients who 
progress will cross over to Erbitux as a single-agent as per Section 7.2.2. 
2. Intolerable toxicity Arm 2 only (follow as per Section 8.4.1). However, if a 
patient on Arm 2 experiences intolerable toxicity to the ICb portion of the 
treatment and is CR, PR, or SD, the patient may continue treatment with Erbitux 
alone after discussion of the individual case with the Study Investigator. Arm 1 
patients who discontinued ICb due to toxicity and who progress will cross over to 
Erbitux as a single-agent as per Section 7.2.2, provided that they have not 
received any intervening nonprotocol therapy. 

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3. Treatment is interrupted for more than 3 weeks on Arm 2 for any reason (follow 
as per Section 8.4.1). If treatment is interrupted for >3 weeks on the ICb portion 
of Arm 1, the patient should discontinue ICb but remain on study, provided that 
no intervening nonprotocol therapy is received, until disease progression when the 
patient will cross over to Erbitux alone as stated in No. 2 above. 
4. For patients who have crossed over to single-agent Erbitux, any treatment 
interruption for more than 3 weeks (follow as per Section 8.4.1) 
5. An intercurrent illness that would, in the judgment of the Investigator, affect 
assessments of clinical status to a significant degree or require discontinuation of 
study treatment (follow as per Section 8.4.1) 
6. Nonprotocol therapy (chemotherapy, radiotherapy, hormonal therapy, 
immunotherapy, or surgery) is administered during study treatment (follow as per 
Section 8.4.1) 
7. Noncompliance with protocol or treatment (follow as per Section 8.4.1) 
8. The patient becomes pregnant (follow as per Section 8.4.1) 
9. The patient refuses to continue treatment (follow as per Section 8.4.1) 
10. Patient completes the treatment portion of the protocol (follow as per 
Section 8.4.2.) 
11. Physician decision (follow as per Section 8.4.1) 
The date of and reason for discontinuation must be noted on the Change of Status page of 
the electronic Case Report Form (eCRF). Every effort should be made to complete the 
appropriate assessments. 
4.5 
REASONS OFF STUDY 
Patients will be considered off study if any of the following occur: 
1. Termination of study by USOR and/or BMS  
2. Patient is lost to follow-up. If a patient does not return for scheduled visits, every 
effort should be made to re-establish contact. In any circumstance, every effort should 
be made to document patient outcome, if possible. 
3. Withdrawal of consent (patient will not be contacted and no further information will 
be collected) 
4. Death 

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The appropriate information must be completed on the Change of Status page of the 
eCRF.  
5 CONCOMITANT THERAPY 
Administration of other chemotherapy or immunotherapy, or hormonal therapy, or 
experimental medications during the study is not allowed. Patients cannot receive 
radiation therapy while receiving study therapy without previous discussion with the SI.  
Supportive care may be administered at the discretion of the Investigator. Replacement 
steroids are permitted. All concomitant treatments, including blood and blood products, 
must be reported on the source documentation (not necessarily in the eCRF). The 
following concomitant medications must be documented on the Con Meds page of the 
eCRF: 
• Blood and blood products 
• Antifungals 
• Prophylactic antibiotics 
• Hematopoietic growth factors 
• Premedications 
• Antibiotics 
• All con meds at baseline 
 
Herbal therapies or alternative therapies are permitted but discouraged. 
5.1 
DRUG-DRUG INTERACTIONS 
5.1.1 
Irinotecan 
The adverse effects of irinotecan, such as myelosuppression and diarrhea, would be 
expected to be exacerbated by other antineoplastic agents having similar adverse effects. 
Patients who have previously received pelvic and/or abdominal irradiation are at 
increased risk of severe myelosuppression following the administration of irinotecan. The 
concurrent administration of irinotecan with irradiation has not been adequately studied 
and is not recommended. 
Lymphocytopenia has been reported in patients receiving irinotecan, and it is possible 
that the administration of dexamethasone as antiemetic prophylaxis may increase the 
likelihood of this effect. However, serious opportunistic infections have not been 
observed, and no complications have specifically been attributed to lymphocytopenia. 
The use of dexamethasone as an antiemetic is allowed. 
Hyperglycemia has also been reported in patients receiving irinotecan. Usually, this has 
been observed in patients with a history of diabetes mellitus or evidence of glucose 
intolerance prior to administration of irinotecan. It is probable that dexamethasone, given 
as antiemetic prophylaxis, contributed to hyperglycemia in some patients. 
The incidence of akathisia in clinical trials was greater (8.5%, 4/47 patients) when 
prochlorperazine was administered on the same day as irinotecan than when these drugs 
were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, 

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however, is within the range reported for use of prochlorperazine when given as a 
premedication for other chemotherapies. 
It would be expected that laxative use during therapy with irinotecan would worsen the 
incidence or severity of diarrhea, but this has not been studied. 
In view of the potential risk of dehydration, secondary to vomiting and/or diarrhea 
induced by irinotecan, the physician may wish to withhold diuretics during dosing with 
irinotecan and certainly during periods of active vomiting or diarrhea. 
5.1.2 
Carboplatin 
The renal effects of nephrotoxic compounds may be potentiated by carboplatin. 
5.1.3 
Erbitux 
A drug interaction study was performed in which Erbitux was administered in 
combination with irinotecan. There was no evidence of any pharmacokinetic interactions 
between Erbitux and irinotecan.  
6 THERAPEUTIC AGENTS 
6.1 
IRINOTECAN (CAMPTOSAR®, IRINOTECAN HCL, CPT-11 PI 5/02) 
Note: since Camptosar goes off patent in 2007 (during the course of this study) the 
generic drug (irinotecan) is used in the dosing schema; CPT-11 is used for 
pharmacokinetics and drug substance discussions. 
Irinotecan (CPT-11, irinotecan HCl, Camptosar®) is a topoisomerase I inhibitor that 
exhibits antitumor activity by inducing irreversible double-strand DNA damage and 
apoptosis. This drug is commercially available. Irinotecan is indicated as a component of 
first line therapy in combination with 5-FU and LV in patients with metastatic cancer of 
the colon or rectum. It is also indicated for patients whose metastatic colon or rectal 
cancer has recurred or progressed following initial 5-FU therapy. 
6.1.1 
Formulation  
Irinotecan is being supplied for this study by Pfizer, Inc. 
Irinotecan is supplied as a sterile, pale yellow, clear, aqueous solution. It is available in 
2 single-dose sizes: 2 mL vials containing 40 mg irinotecan and 5 mL vials containing 
100 mg irinotecan. Each milliliter of solution contains 20 mg of irinotecan (on the basis 
of the trihydrate salt), 45 mg of sorbitol NF powder, and 0.9 mg of lactic acid, USP. The 
pH of the solution has been adjusted to 3.5 (range, 3.0-3.8) with sodium hydroxide or 
hydrochloric acid. 

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6.1.2 
Storage and Stability  
Vials of irinotecan injection should be stored at a controlled room temperature  
(15° to 30°C, 59° to 86°F) and protected from light. It is recommended that the vial (and 
backing/plastic blister) remain in the carton until the time of use. 
Once diluted, the solution is physically and chemically stable for up to 24 hours at room 
temperature (approximately 25°C) and in ambient fluorescent lighting. Diluted solutions 
stored at refrigerated temperatures (approximately 2° to 8°C, 36° to 46°F) and protected 
from light are physically and chemically stable for 48 hours if prepared in a certified 
sterile hood. If the diluted solutions are prepared at the counter, it is advisable to use the 
refrigerated solution within 24 hours due to possible microbial contamination. Freezing 
irinotecan and admixtures of irinotecan may result in precipitation of the drug and should 
be avoided. Diluted solutions should be used within 6 hours if kept at room temperature 
(15° to 30°C, 59° to 86°F). Other drugs should not be added to the infusion solution. 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration when solution and container permit. 
6.1.3 
Preparation and Administration  
Care should be exercised in the handling and preparation of infusion solutions prepared 
from irinotecan injection. The use of gloves is recommended. If a solution of irinotecan 
contacts the skin, wash the skin immediately and thoroughly with soap and water. If 
irinotecan contacts the mucous membranes, flush thoroughly with water.  
If possible, irinotecan diluted solution should be prepared in a certified sterile hood. Vial 
contents should be inspected for particulate matter and when drug product is withdrawn 
from vial into syringe. Irinotecan injection must be diluted prior to infusion. Irinotecan 
should be diluted in 5% Dextrose injection, USP, to a final concentration range of  
0.12 to 2.8 mg/mL. In most clinical trials, irinotecan was administered in 250 mL to 
500 mL of 5% Dextrose injection, USP.  
Irinotecan should be administered by intravenous infusion over 90 minutes. 
6.1.4 
Pharmacokinetics 
Pharmacokinetic parameters for irinotecan (CPT-11) and its active metabolite SN38 
following a 90-minute infusion of CPT-11 at dose levels of 125 and 340 mg/m2 were 
determined in 2 clinical studies in patients with solid tumors. Pharmacokinetic data are 
summarized in Table 4. 

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Table 4. Summary of Mean (±SD) CPT-11 and SN38 Pharmacokinetic Parameters 
in Patients with Solid Tumors 
 
CPT-11 
SN38 
Dose 
(mg/m2) 
Cmax 
(ng/mL) 
AUC0-24 
(ng⋅h/mL) 
T1/2 
(h) 
Vz 
(L/m2) 
CL 
(L/h/m2) 
Cmax 
(ng/mL) 
AUC0-24 
(ng⋅h/mL) 
T1/2 
(h) 
125 
(N=64) 
1,660 ± 
797 
10,200 ± 
6,027 
5.8a ± 
0.7 
110 ± 
48.5 
13.3 ± 
6.01 
26.3 ± 
11.9 
229 ± 108 
10.4a ± 
3.1 
340 
(N=6) 
3,392 ± 
874 
20,604 ± 
6,027 
11.7b ± 
1.0 
234 ± 
69.6 
13.9 ± 
4.00 
56.0 ± 
28.2 
474 ± 245 
21.0b ± 
4.3 
Cmax 
Maximum plasma concentration 
AUC0-24 
Area under the plasma concentration-time curve from time 0 to 24 hours after the end of the 90-minute 
infusion 
T1/2 
Terminal elimination half-life 
Vz 
Volume of distribution of terminal elimination phase 
CL 
Total systemic clearance 
a 
Plasma specimens collected for 24 hours following the end of the 90-minute infusion. 
b 
Plasma specimens collected for 48 hours following the end of the 90-minute infusion. Because of the longer 
collection period, these values provide a more accurate reflection of the terminal elimination half-lives of 
CPT-11 and SN38. 
6.1.5 
Adverse Effects 
A Phase III study investigated the addition of irinotecan to a 5-FU + LV regimen versus 
administration of irinotecan alone in patients with metastatic colorectal cancer. Table 5 
lists the adverse events that were reported with irinotecan treatment alone. 
Death 
Thirteen patients (5.8%) died. Two of these deaths (0.9%) were treatment-related 
(neutropenic fever). 
Hematologic 
Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a 
significantly greater likelihood of experiencing first-course Grade 3 or 4 neutropenia than 
those with bilirubin levels less than 1.0 mg/dL (50% vs. 18%). In addition, neutropenic 
fever (concurrent Grade 4 neutropenia and Grade 2 or greater fever) occurred in 3% of 
the patients. 

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Table 5. 
Adverse Events Attributed to CPT-11 (Irinotecan) in 
Patients with Metastatic Colorectal Cancer 
 
Grade 1-4 
Grade 3-4 
Total: Adverse Events 
99.6 
45.7 
 
 
 
Gastrointestinal 
 
 
 
Diarrhea 
 
 
 
Late 
83.0 
31.0 
 
 
Grade 3 
0 
18.4 
 
 
Grade 4 
0 
12.6 
 
Early 
43.0 
6.7 
 
Nausea 
81.6 
16.1 
 
Abdominal Pain 
67.7 
13.0 
 
Vomiting 
62.8 
12.1 
 
Anorexia 
43.9 
7.2 
 
Constipation 
32.3 
0.4 
 
Mucositis 
29.6 
2.2 
Hematologic 
 
 
 
Neutropenia 
96.4 
31.4 
 
 
Grade 3 
0 
19.3 
 
 
Grade 4 
0 
12.1 
 
Leukopenia 
96.4 
21.5 
 
Anemia  
96.9 
4.5 
 
Neutropenic Fever 
0 
5.8 
 
Thrombocytopenia 
96.0 
1.7 
 
Neutropenic Infection 
0 
2.2 
Body as a Whole 
 
 
 
Asthenia 
69.1 
13.9 
 
Pain 
22.9 
2.2 
 
Fever 
43.5 
0.4 
 
Infection 
13.9 
0.4 
Metabolic and Nutritional 
 
 
 
Increased Bilirubin 
83.9 
7.2 
Dermatologic 
 
 
 
Exfoliative Dermatitis 
0 
0 
 
Rash 
14.3 
0.4 
 
Alopecia 
46.1 
0 
Respiratory 
 
 
 
Dyspnea 
22.0 
2.2 
 
Cough 
20.2 
0.4 
 
Pneumonia 
3.6 
1.3 
Neurologic 
 
 
 
Dizziness 
21.1 
1.8 
 
Somnolence 
9.4 
1.3 
 
Confusion 
2.7 
0 
Cardiovascular 
 
 
 
Vasodilation 
9.0 
0 
 
Hypotension 
5.8 
1.7 
 
Thromboembolic Events 
5.4 
0 
Grading based on CTC Version 1.0 

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Teratogenic 
Irinotecan may cause fetal harm when administered to a pregnant woman. Radioactivity 
related to 14C-irinotecan (CPT-11) crosses the placenta of rats following IV 
administration of 10 mg/kg (which in separate studies produces a CPT-11 Cmax and AUC 
about 3 and 0.5 times, respectively, the corresponding values in patients administered 
125 mg/m2). Administration of 6 mg/kg/day intravenous CPT-11 to rats and rabbits 
during the period of organogenesis was embryotoxic, as characterized by increased post-
implantation loss and decreased numbers of live fetuses. CPT-11 was teratogenic in rats 
at doses greater than 1.2 mg/kg/day and in rabbits at 6.0 mg/kg/day. Teratogenic effects 
included a variety of external, visceral, and skeletal abnormalities. CPT-11 administration 
to rat dams for the period following organogenesis through weaning at doses of 
6 mg/kg/day caused decreased learning ability and decreased female body weights in the 
offspring.  
Pregnancy 
There are no adequate and well-controlled studies of irinotecan in pregnant women. If the 
drug is used during pregnancy, or if the patient becomes pregnant while receiving this 
drug, the patient should be apprised of the potential hazard to the fetus. Women of 
childbearing potential should be advised to avoid becoming pregnant while receiving 
treatment with irinotecan. 
Nursing Mothers 
Radioactivity appeared in rat milk within 5 minutes of intravenous administration of 
radiolabeled CPT-11 and was concentrated up to 65-fold at 4 hours after administration 
relative to plasma concentrations. It is recommended that nursing be discontinued while 
receiving therapy with CPT-11. 
Please see the package insert for additional adverse events. 
6.2 
CARBOPLATIN (PARAPLATIN® OR EQUIVALENT PI 6/2001) 
Carboplatin (Paraplatin for injection) is a platinum coordination compound that is used as 
a cancer chemotherapeutic agent. Carboplatin is indicated for the treatment of advanced 
ovarian cancer. Carboplatin is commercially available from Bristol-Myers Squibb. 
6.2.1 
Formulation 
Carboplatin (Paraplatin for injection) is a platinum coordination compound; the chemical 
name is platinum, diammine [1,1-cyclobutanedicarboxylato (2-)-0, 0']-,(SP-4-2). 
Carboplatin is a crystalline powder with the molecular formulation C6H12N2O4Pt and a 
molecular weight of 371.25. 

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6.2.2 
Storage and Stability  
Unopened vials of carboplatin should be stored at 25°C (77°F); excursions are permitted 
to 15° - 30°C (59°-86°F). Unopened vials should be protected from light. Solutions for 
infusion should be discarded 8 hours after preparation. 
Unopened vials of carboplatin are stable for the life indicated on the package. When 
stored at the temperatures indicated above and protected from light. When prepared as 
directed, carboplatin solutions are stable for 8 hours at room temperature (25°C). Since 
no antibacterial preservative is contained in the formulation, it is recommended that 
carboplatin solutions be discarded 8 hours after dilution. Parenteral drugs should be 
inspected visually for particulate matter and discoloration prior to administration. 
6.2.3 
Preparation and Administration  
Immediately before use, the content of each vial must be reconstituted with either Sterile 
Water for Injection, USP; 5% Dextrose in Water (D5W); 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 (D5W) 
or 0.9% Sodium Chloride Injection, USP 
6.2.4 
Pharmacokinetics  
Carboplatin, like cisplatin, produces predominantly interstrand DNA cross-links rather 
than DNA-protein cross-links. This effect is apparently cell-cycle nonspecific. The 
aquation of carboplatin, which is thought to produce the active species, occurs at a slower 
rate than in the case of cisplatin. Despite this difference, it appears that both carboplatin 
and cisplatin induce equal numbers of drug-DNA cross-links, causing equivalent lesions 
and biological effects. The differences in potencies for carboplatin and cisplatin appear to 
be directly related to the difference in aquation rates.  
In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of 
intact carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 
300 to 500 mg/m2 of carboplatin. The initial plasma half-life (alpha) was found to be  
1.1 to 2 hours (N = 6), and the post distribution plasma half-life (beta) was found to be 
2.6 to 5.9 hours (N = 6). The total body clearance, apparent volume of distribution and 
mean residence time for carboplatin are 4.4 L/ hour, 16 L and 3.5 hours, respectively. The 
Cmax values and areas under the plasma concentration vs. time curves from 0 to infinity 
(AUC 0-∞) increase linearly with dose, although the increase was slightly more than dose 
proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing 
range studied (300-500 mg/m2).  

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Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, 
ultrafilterable platinum-containing species other than carboplatin are present in plasma. 
However, platinum from carboplatin becomes irreversibly bound to plasma proteins and 
is slowly eliminated with a minimum half-life of 5 days.  
The major route of elimination of carboplatin is renal excretion. Patients with creatinine 
clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine 
within 12 hours and 71% of the dose within 24 hours. All of the platinum in the 24-hour 
urine is present as carboplatin. Only 3 to 5% of the administered platinum is excreted in 
the urine between 24 and 96 hours. There are insufficient data to determine whether 
biliary excretion occurs.  
In patients with creatinine clearances below 60 mL/min the total body and renal 
clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin 
dosages should therefore be reduced in these patients.  
6.2.5 
Adverse Effects 
Adverse event information was compiled from studies of patients with ovarian cancer and 
compared 2 cisplatin combinations (NCIC study and SWOG study).30 The pattern of 
toxicity exerted by the carboplatin-containing regimen was significantly different from 
that of the cisplatin-containing combinations. Differences between the 2 studies may be 
explained by different cisplatin dosages and by different supportive care. The 
carboplatin-containing regimen induced significantly more thrombocytopenia and, in 
1 study, significantly more leukopenia and more need for transfusional support. The 
cisplatin-containing regimen produced significantly more anemia in 1 study. However, no 
significant differences occurred in incidences of infections and hemorrhagic episodes.  
Nonhematologic toxicities (emesis, neurotoxicity, ototoxicity, renal toxicity, 
hypomagnesemia, and alopecia) were significantly more frequent in the cisplatin-
containing arms.  
Data from a single-agent study is summarized in Table 6. 
 

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Table 6. 
Adverse Experiences in Ovarian Cancer 
Patients Treated with Carboplatin 
Event 
Percent 
Bone marrow 
 
Thrombocytopenia (<100,000/mm3) 
62 
Thrombocytopenia (<50,000/mm3) 
35 
Neutropenia (<2,000 cells/mm3) 
67 
Neutropenia (<1,000 cells/mm3) 
21 
Leukopenia (<4,000/mm3) 
85 
Leukopenia (<2,000/mm3) 
26 
Anemia (<11 g/dL) 
90 
Anemia (<8 g/dL) 
21 
Infections 
5 
Bleeding 
5 
Transfusions 
44 
Gastrointestinal 
 
Nausea and vomiting 
92 
Vomiting 
81 
Other GI side effects 
21 
Neurologic 
 
Peripheral neuropathies 
6 
Ototoxicity 
1 
Other sensory side effects 
1 
Central neurotoxicity 
5 
Renal 
 
Serum creatinine elevations 
10 
Blood urea elevations 
22 
Hepatic 
 
Bilirubin elevations 
5 
SGOT elevations 
19 
Alkaline phosphatase elevations 
37 
Electrolyte loss 
 
Sodium 
47 
Potassium 
28 
Calcium 
31 
Magnesium 
43 
Other side effects 
 
Pain 
23 
Asthenia 
11 
Cardiovascular 
6 
Respiratory 
6 
Allergic 
2 
Genitourinary 
2 
Alopecia 
2 
Mucositis 
1 
Please see the package insert for additional adverse events. 
6.3 
CETUXIMAB (ERBITUX™ PI 2/04) 
Cetuximab is an antiEGFR 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 

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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. 
6.3.1 
Supplier/How Supplied 
Bristol-Myers Squibb (BMS) will supply Erbitux (cetuximab) free of charge to the 
patient. The product is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may 
contain a small amount of easily visible, white, amorphous cetuximab particulates. Each 
single-use 50-mL vial contains 100 mg of cetuximab at a concentration of 2 mg/mL and 
is formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 
1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL sodium phosphate 
monobasic monohydrate, and Water for injection, USP. 
6.3.2 
Packaging and Labeling 
Cetuximab for injection will be supplied by BMS in single-use, ready-to-use 50-mL vials 
containing 2 mg/mL of product. 
6.3.3 
Handling and Dispensing of Erbitux 
Erbitux must be dispensed only from official study sites by authorized personnel 
according to local regulations. Erbitux should be stored in a secure area according to 
local regulations. It is the responsibility of the Investigator to ensure that study drug is 
only dispensed to study patients. 
6.3.4 
Storage Requirement/Stability 
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). DO NOT FREEZE. 
Increased particulate formation may occur at temperatures at or below 0°C. This product 
contains no preservatives. Preparations of Erbitux in infusion containers are chemically 
and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) or up to 8 hours 
at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining 
solution in the infusion container after 8 hours at controlled room temperature or after 
12 hours at 2° to 8° C. Discard any unused portion of the vial. 
6.3.5 
Preparation and Administration 
Erbitux must not be administered as an IV push or bolus. 
Erbitux must be administered with the use of a low protein binding 0.22-micrometer in-
line filter. 
Erbitux 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. 

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Erbitux 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 Erbitux into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (eg, Baxter Intravia ®), ethylene vinyl acetate bags (eg, Baxter 
Clintec®), DEHP plasticized PVC bags (eg, Abbott Lifecare®), or PVC bags. 
• Repeat procedure until the calculated volume has been put in to the container. Use 
a new needle for each vial. 
• Administer through a low protein binding 0.22-micrometer in-line filter (placed as 
proximal to the patient as practical). 
• Affix the infusion line and prime it with Erbitux before starting the infusion. 
• Maximum infusion rate should not exceed 5 mL/min. 
• Use 0.9% saline solution to flush line at the end of infusion. 
Syringe Pump: 
• Draw up the volume of a vial using a sterile syringe attached to an appropriate 
needle (a vented spike may be used). 
• Place the syringe into the syringe driver of a syringe pump and set the rate. 
• Administer through a low protein binding 0.22-micrometer in-line filter rated for 
syringe pump use (placed as proximal to the patient as practical). 
• Connect up the infusion line and start the infusion after priming the line with 
Erbitux. 
• 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. 
• Erbitux should be piggybacked to the patient’s infusion line. 
Following the Erbitux infusion, a 1-hour observation period is recommended. 
6.3.6 
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. 
Otherwise, opened vials must be returned to BMS for disposal. For questions regarding 
Erbitux destruction please contact BMS at 866 339-4267 or 203 677-7017. 
Erbitux therapy should be used with caution in patients with known hypersensitivity to 
Erbitux (cetuximab), murine proteins, or any component of this product. 
It is recommended that patients wear sunscreen and hats and limit sun exposure while 
receiving Erbitux as sunlight can exacerbate any skin reactions that may occur. 

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6.3.7 
Adverse Effects 
Adverse effects are summarized in Section 1.5.4 
Anaphylaxis-like infusion reactions 
There have been reports of rare episodes of anaphylactic-like infusion reactions to 
Erbitux. If patients experience such reactions the following procedures should be 
followed:  
Severe infusion reactions require the immediate interruption of Erbitux therapy and 
permanent discontinuation from further treatment. 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 clinical trials, mild to moderate infusion reactions were managed by slowing the 
infusion rate of Erbitux and by continued use of antihistamine premedications (eg, 
diphenhydramine) in subsequent doses. If the patient experiences a mild or moderate 
(Grade 1 or 2) infusion reaction, the infusion rate should be permanently reduced 
(slowed) by 50%. For grade 1 or 2 reactions manifesting only as delayed drug fever, 
maintain the Erbitux dose and infusion rate. Consideration should be given to 
administration of acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) prior 
to the subsequent Erbitux infusion if not contraindicated in subjects. Dose and schedule 
of these agents is entirely at the Investigator’s discretion. 
Emergency medication and oxygen (and note any specifics in BMS protocol) must be 
available in the infusion room during the time that patients are receiving Erbitux dosing. 
Note: Erbitux should be immediately and permanently discontinued in patients who 
experience severe (Grade 3 or 4) infusion reactions. 
Symptomatic Hypomagnesemia 
There have been reports of patients treated with cetuximab occasionally developing a 
magnesium-wasting syndrome with inappropriate urinary excretion. A 34-year-old male 
patient with metastatic colon cancer developed profound fatigue and symptomatic 
hypocalcemia and hypomagnesemia while receiving cetuximab and irinotecan, but no 
other agents with the potential to cause magnesium wasting. The patient required 
intravenous magnesium supplementation for the duration of cetuximab therapy, but 
electrolyte abnormalities resolved upon discontinuation of treatment. This case prompted 
investigators to review serum chemistry reports for a consecutive case series of 
154 colorectal cancer patients treated with cetuximab.30a During cetuximab treatment, 
34 (22%) patients had at least 1 serum magnesium measurement during cetuximab 
treatment, and 6 had Grade 3 (<0.9 mg/dL) and 2 had Grade 4 (<0.7 mg/dL. The 
investigators suggest that because EGFR is strongly expressed in the kidney that the 
EGFR blockage exerted by cetuximab may interfere with magnesium transport. They 

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recommend that serum magnesium levels be measured and replenished as necessary 
during cetuximab therapy whenever fatigue or hypocalcemia is encountered. 
Please see the package insert for additional adverse events. 
7 INVESTIGATIONAL PLAN 
7.1 
REGISTRATION PROCEDURES 
Written documentation of full, noncontingent IRB approval must be on file before a 
patient can be registered. The registration process begins when the coordinator has 
obtained a signed informed consent. Before calling the Central Research office please 
enter patient demographics into the Clinical Trial Management System (CTMS); this is 
the Web-based intranet system for the delivery of trial information across USOR. 
Entering a patient into CTMS does not signify that you have registered the patient in the 
study. If you have any difficulty with CTMS please contact the Research Information 
Technology office at (832) 348-5184.  
Secondly, the coordinator must fax the signed consent form and current registration form 
(make sure to use the latest version of the registration form, check the footer at the 
bottom of the page of the registration form) to the Central Research Office at  
(832) 601-6462. If within 30 minutes an e-mail confirming registration is not received, 
then the Coordinator will call the Registration Coordinator at (832) 348-5964 (please note 
new number) to confirm receipt. An accession number is directly assigned once the 
patient is found eligible. Treatment must begin within 5 working days after the 
patient’s registration on the study.  
Lastly, the Registration Coordinator will enter the accession number into the CTMS/eRT 
databases. This will constitute your registration confirmation. The Registration 
Coordinator will send a confirmation of registration via e-mail. Please make a copy and 
attach to your file.  
The complete form will provide the following information: 
1. Protocol Number 
2. Study Investigator Identification 
• Institutional Name and/or Affiliate 
• Study Investigator’s Name 
3. Patient Identification 
• Initials 
• Patient Identification Number, obtained from the CTMS 
• Patient Accession Number, given verbally over the telephone by the Registration 
Coordinator, and/or via e-mail. 
4. Demographics, including date of birth, performance status, and race 
5. Eligibility Verification  
• Patients must meet all of the eligibility requirements 
6. Date of planned Start of Treatment  

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It is the policy of the USOR Research Office to allow the SI of Investigator-Initiated 
studies the opportunity to review and grant exceptions for minor deviations in eligibility, 
in order to maximize patient accrual without jeopardizing patient safety or scientific 
integrity of these studies. Examples might include minor deviations of baseline labs, 
timing of prior treatment or tests, etc. It is recognized that these questions arise 
frequently. The procedure to be followed is for the Investigator or his/her representative 
(eg, research nurse) to e-mail the request to the SI for an exception. The SI would then 
make a determination, which is binding. In no instance should this exception constitute a 
safety issue for the patient or a significant deviation from the scientific purpose of the 
study. All requests for exceptions and the decision of the SI will be recorded by the 
USOR Research Office and then be reviewed on a regular basis by the appropriate 
disease committee chair and any other interested committees. 
7.2 
STUDY TREATMENT ADMINISTRATION 
7.2.1 
Premedications 
Irinotecan 
There is no required premedication for the administration of irinotecan. Premedication for 
irinotecan is at the discretion of the Treating Physician. 
Erbitux 
All patients should be premedicated with diphenhydramine hydrochloride 50 mg (or an 
equivalent antihistamine) and 10 mg dexamethasone by IV given 30-60 minutes prior to 
the first dose of Erbitux. Premedication may be administered prior to subsequent doses, at 
the Investigator’s discretion; the dose of diphenhydramine (or a similar agent) may be 
reduced. 
Carboplatin 
No premedication is required prior to the administration of carboplatin. 
7.2.2 
Chemotherapy and Erbitux 
The initial dose of Erbitux 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 
Erbitux must never exceed 5 mL/min. Patients must be continuously observed during 
the infusion for signs of anaphylaxis-like infusion reactions.  
Note: Should anaphylaxis occur, all emergency medications and supplies necessary to 
treat the patient should be kept in the infusion room.  
Dose levels for Erbitux are summarized in Table 7: 

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Table 7. 
Erbitux Dose Levels 
Does Level 
Weekly Erbitux dose 
Starting dose 
250 mg/m2 
Dose Level -1 
200 mg/m2 
Dose Level -2 
150 mg/m2 
Patients will be closely monitored for treatment-related adverse events, especially 
infusion reactions (see Section 5.2.1), during the infusion and the postinfusion 
observation hour. For the initial Erbitux infusion, vital signs should be monitored 
preinfusion, 1/2 hour into the infusion, at the end of the infusion and 1 hour postinfusion. 
For subsequent infusions, vital signs should be taken pre- and postinfusion; however, it is 
recommended that the patient be observed for 1 hour postinfusion. 
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. 
Note: Caution must be exercised with every Erbitux infusion, as there were patients 
who experienced their first severe infusion reaction during later infusions. 
At each cycle, patients must have the following hematologic values to receive their 
planned dose: ANC >1000 and platelets >100,000. Treatment will be delayed until counts 
are at these levels. Patients can resume treatment at the previous dose if counts recover, 
or will be given reduced doses (see Table 10): irinotecan 70 mg/m2 and carboplatin 
AUC=1.5. The Erbitux dose will not be reduced. 
Arm 1 
1. Patients will receive 90 mg/m2 of irinotecan administered IV during a 90-minute 
period followed by carboplatin area under the curve (AUC)= 2.0 administered IV 
during a 30-60 minute period on Days 1, 8 of a 21 day cycle 
2. One cycle of treatment is defined as 2 weeks of treatment, followed by 1 week of rest  
3. Successive cycles will be initiated every 3 weeks, and will be continued until a 
patient shows evidence of disease progression or intolerable toxicity. 
Patients whose disease progresses on ICb alone or whose disease progresses after an ICb 
drug holiday, provided that they have not had any intervening nonprotocol therapy, will 
cross over to receive single-agent weekly Erbitux at the same dosage as described in 
Arm 2 of the study until disease progression. Arm 1 patients may also stop either 
irinotecan or carboplatin due to agent-related toxicity and continue on the other agent 
alone after discussion with the Study Investigator. 
Arm 2 
1. Patients will receive Erbitux 400 mg/m2 IV over 120 min for their first dose and 
250 mg/m2 IV over 60 min weekly thereafter. Following therapy with Erbitux, 

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patients will receive 90 mg/m2 of irinotecan administered IV during a 90-minute 
period followed by carboplatin area under the curve (AUC)= 2.0 administered IV 
during a 30-60 minute period on Days 1, 8 of a 21 day cycle.  
2. One cycle of treatment is defined as 2 weeks of chemotherapy treatment, followed by 
1 week of rest. Erbitux is given weekly (Day 1, 8, and 15) without interruption. 
3. Successive cycles will be initiated every 3 weeks, and will be continued through until 
a patient shows evidence of disease progression or intolerable toxicity. 
An Arm 2 patient may also stop either irinotecan or carboplatin due to agent-related 
toxicity and continue on the other agent in combination with Erbitux after discussion with 
the Study Investigator. 
The treatment schema is summarized in Table 8. 
 
Table 8. 
Treatment Schema 
Cycle 
Week 
Day 
Arm 1 
90 mg/m2 IV irinotecan 
AUC=2.0 IV carboplatin 
Arm 2 
Erbitux 250 mg/m2 IV  
90 mg/m2 IV irinotecan 
AUC=2.0 IV carboplatin 
1 
1 
a 
a 
(400 mg/m2 for 1st Erbitux 
dose only) 
2 
8 
a 
a 
 
1 
3 
15 
Rest 
Erbitux only 
*Day 22 is Day 1 of the next cycle 
Note: Patients whose disease progresses on ICb alone (Arm 1) or whose disease progresses after an ICb 
drug holiday, provided that they have not had any intervening nonprotocol therapy, will cross over to 
receive single-agent weekly Erbitux at the same dosage as described in Arm 2 of the study until disease 
progression. 
Drug order:  
Arm 1: irinotecanÆ carboplatin 
Arm 2: ErbituxÆ irinotecanÆ carboplatin 
Note: H1/H2 Blockers will be given with the first dose of Erbitux. Premedication may be 
administered prior to subsequent doses at the Treating Physician’s discretion as per 
section 7.2.1. 
7.2.3 
Treatment Delay 
1. Treatment may be delayed no more than 3 weeks on Arm 2 (not counting rest weeks) 
to allow recovery from acute toxicity. If treatment is interrupted for >3 weeks on the 
ICb portion of Arm 1, the patient should discontinue ICb but remain on study, 
provided that no intervening nonprotocol therapy is received, until disease 
progression when the patient will cross over to Erbitux alone. 

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2. Patients on Arm 2 or Arm 1 patients who have crossed over who are off study 
treatment for more than 3 weeks (not counting rest weeks) due to toxicities will be 
considered off study. 
3. Administration of study drugs must be as scheduled above; anything else must be 
documented as a deviation (minor). 
7.2.4 
Dose Modification for Toxicity 
Dose reductions are to be made according to the system showing the greatest degree of 
toxicity. Toxicities will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 as linked in Appendix VI.  
If a treatment day variation is needed for reasons other than toxicity, an attempt should be 
made to keep the variation within the following parameters: ±3 days for 21-day cycles. 
Delays within this window are NOT a deviation.  
Two dose reductions for hematological toxicities will be permitted before a patient is 
taken off study. Two dose reductions are allowed if the patient experiences recurrent 
Grade 3 nonhematologic toxicities, including neurotoxicity. A patient will be taken off 
study for a second occurrence of a Grade 4 nonhematologic toxicity. 
7.2.4.1 Nonhematologic Toxicity 
1. For nonhematologic toxicities that are ≤Grade 2, manage symptomatically if possible, 
and retreat without dose reduction.  
2. For nonhematologic, nonneurologic Grade 3 or 4 toxicities (excluding nausea, 
vomiting and alopecia), the treatment should be withheld until resolution to <Grade 1 
toxicity.  
3. Treatment should be resumed as per the recommendations in Table 9 and Table 10. 
These reductions are permanent. 
4. If the treatment was withheld for more than 3 weeks, the patient will be taken off 
study treatment. 
Table 9 summarizes dose reductions for nonhematological, nonneurologic toxicities.  
Table 9. 
Dose Reductions for Nonhematological Toxicities 
Toxicity Grade 
Irinotecan 
Carboplatin 
1-2 
Treat symptomatically* 
Treat symptomatically* 
3-4 First occurrence (except 
nausea and vomiting) 
Reduce dose to 
70 mg/m2 
Reduce dose to 
AUC = 1.5 
3 Second occurrence** 
(except nausea and vomiting) 
Reduce to 60 mg/m2 
Reduce dose to 
AUC = 1.0 
* Loperamide 1 after each loose stool up to 6 a day for Grade 1-2 diarrhea 
**Remove patient from study for second occurrence Grade 4 toxicity in spite of dose reduction 

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Treatment for nausea and vomiting will be at the discretion of the Treating Physician. 
For febrile neutropenia 
If febrile neutropenia develops, treat with Neulasta on the following cycle (6 mg, 
subcutaneously, Day 9). If a second episode occurs despite treatment with Neulasta, 
decrease irinotecan to 70 mg/m2 and carboplatin to AUC=1.5. 
7.2.4.1.1 
NONHEMATOLOGICAL TOXICITIES SPECIFIC FOR ERBITUX 
Please refer to Section 7.2.4.2.1 for management of infusion reactions, pulmonary 
toxicity, and dermatological toxicity, which are specific to Erbitux. 
7.2.4.2 Hematologic Toxicity 
Treatment decisions and dose reductions should be made based on the ANC and platelet 
counts on the scheduled day of treatment. Patients should not be treated on Day 1 if ANC 
<1000/μ/L or platelets <100K. If a patient’s counts are to low to treat, then either add 
Neulasta to the next cycle if the patient’s ANC have failed to recover or reduce the dose 
of ICb according to Table 10 once the counts recover to treatable levels. 
For patients who are responding to ICb with or without Erbitux but who develop 
cumulative thrombocytopenia (platelets fail to recover to 100K on Day 1 despite 2 dose 
reductions of carboplatin), carboplatin should be discontinued and patients should be 
treated with either irinotecan alone or irinotecan and Erbitux until disease progression. If 
doses must be reduced a third time, contact the SI. 
Table 10. 
Dose Reductions for Hematological Toxicity Day 8 of Each Cycle* 
Value on Day 8 
Irinotecan  
Carboplatin 
ANC >1000/µL Platelets >100K 
90 mg/m2 
AUC=2.0 
1000>ANC >750/µL** and/or 
75K <platelets<100K 
Reduce dose to 70 mg/m2*** 
Reduce dose to AUC=1.5*** 
If dose has already been reduced 
once 
Reduce dose to 60 mg/m2*** 
Reduce dose to AUC=1.0*** 
ANC <750/µL and/or platelets<75K 
Hold Day 8 chemotherapy. Do not make up chemotherapy. 
*  
The dose reductions shown in this table can also be used for Day 1. 
**  
Neulasta can be given on Day 9. 
*** 
Reduced doses will not be re-escalated. If a patient requires a dose reduction on Day 8 of a cycle, 
continue therapy with this dose reduction. 
7.2.4.2.1 
MANAGEMENT OF ADVERSE EVENTS SPECIFIC FOR ERBITUX  
There will be no dose level reductions below a weekly dose of 150 mg/m2.  
Adverse events should be coded according to CTCAE Version 3.0. Infusion reactions 
should be graded according to allergic reaction/hypersensitivity. 
 

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Management of Infusion Reactions 
Severe infusion reactions require the immediate interruption of Erbitux therapy and 
permanent discontinuation from further treatment. 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 clinical trials, mild to moderate infusion reactions were managed by slowing the 
infusion rate of Erbitux and by continued use of antihistamine premedications (eg, 
diphenhydramine) in subsequent doses. If the patient experiences a mild or moderate 
(Grade 1 or 2) infusion reaction, the infusion rate should be permanently reduced 
(slowed) by 50%. For grade 1 or 2 reactions manifesting only as delayed drug fever, 
maintain the Erbitux dose and infusion rate. Consideration should be given to 
administration of acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) prior 
to the subsequent Erbitux infusion if not contraindicated in subjects. Dose and schedule 
of these agents is entirely at the Investigator’s discretion. 
Note: Erbitux should be immediately and permanently discontinued in patients who 
experience severe (Grade 3 or 4) infusion reactions. 
Management of Pulmonary Toxicity 
In the event of acute onset (Grade ≥2) or worsening pulmonary symptoms, which are not 
thought to be related to underlying cancer, Erbitux therapy should be interrupted and a 
prompt investigation of these symptoms should occur. Erbitux treatment should not be 
resumed until these symptoms have resolved to Grade 1. If interstitial lung disease is 
confirmed, Erbitux should be discontinued and the patient should be treated 
appropriately.  
Treatment of Isolated Drug Fever 
In the event of isolated drug fever, the Investigator must use clinical judgment to 
determine if the fever is related to the study drug or to an infectious etiology. 
If a patient experiences isolated drug fever, for the next dose, pretreat with 
acetaminophen or nonsteroidal anti-inflammatory agent (at Treating Physician’s 
discretion), repeat antipyretic dose 6 and 12 hours after cetuximab infusion. The infusion 
rate will remain unchanged for future doses. 
If patient experiences recurrent isolated drug fever following premedication and post-
dosing with an appropriate antipyretic, the infusion rate for subsequent dosing should be 
50% of previous rate. If fever recurs following infusion rate change, the Investigator 
should assess the patient’s level of discomfort with the event and use clinical judgment to 
determine if the patient should receive further cetuximab. 

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Management of Dermatologic Toxicity 
Patients developing dermatologic toxicities while receiving Erbitux should be monitored 
for the development of inflammatory or infectious sequelae, and appropriate treatment of 
these symptoms initiated. Dose modifications of any future Erbitux infusions should be 
instituted in case of severe (Grade 3) acneform rash. Treatment with topical and/or oral 
antibiotics should be considered; topical corticosteroids are not recommended. 
If a patient experiences severe acneform rash, Erbitux treatment adjustments should be 
made according to the following table. In patients with mild and moderate skin toxicity, 
treatment should continue without dose modification. 
Table 11. 
Erbitux Dose Modification Guidelines – Dermatologic Toxicity 
Grade 3 
Acneform Rash 
Erbitux 
Outcome 
Erbitux Dose 
Modification 
1st occurrence 
Delay infusion 
1 to 2 weeks 
Improvement 
Continue at 250 mg/m2 
 
 
No Improvement 
Discontinue Erbitux 
2nd occurrence 
Delay infusion 
1 to 2 weeks  
Improvement 
Reduce dose to 200 mg/m2 
 
 
No Improvement 
Discontinue Erbitux 
3rd occurrence 
Delay infusion 
1 to 2 weeks 
Improvement 
Reduce dose to 150 mg/m2 
 
 
No Improvement 
Discontinue Erbitux 
4th occurrence 
Discontinue Erbitux 
 
 
7.3 
TOXICITY 
Toxicities will be graded and reported according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 3.0 as linked in Appendix VI. This 
document can also be downloaded from the Cancer Therapy Evaluation Program (CTEP) 
home page <http://ctep.info.nih.gov>. 
8 SCHEDULE OF ASSESSMENTS 
The schedule of assessments for the trial is shown in Appendix V. If a required 
observation or procedure is missed, documentation is required in the source records on 
the Protocol Deviation Form (available on CTMS) and on the eCRF, to explain the 
reason for this protocol deviation.  

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8.1 
PRESTUDY ASSESSMENTS 
The following assessments will be performed within 3 weeks prior to registration 
unless otherwise specified.  
1. A signed Patient Informed Consent Form must be obtained.  
2. A signed Patient Authorization (HIPAA) Form has been obtained.  
3. It has been confirmed that the patient meets all inclusion criteria and none of the 
exclusion criteria.  
4. A complete medical history (review of body systems, excluding gynecological and 
rectal exams) 
5. A complete physical examination (including height, weight, vital signs, review of 
body systems, and calculation of BSA).  
6. Assessment of PS on the ECOG scale (Appendix I)  
7. CBC with differential and platelet count  
8. Complete metabolic profile (CMP), including: serum chemistries (creatinine, glucose, 
total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total 
bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium) 
9. Assessment of magnesium (baseline) 
Note: Careful monitoring of magnesium is necessary to avoid magnesium-wasting 
syndrome that has been reported in patients receiving cetuximab in combination 
with irinotecan and carboplatin. 
10. Calculation of creatinine clearance (ClCr) using the Cockcroft-Gault formula 
(Appendix III)  
Note: Do not recalculate the carboplatin dose based on increases or decreases in 
ClCr of <20%. 
11. Females of childbearing potential (premenopausal women and peri-menopausal 
women who have been amenorrheic <12 months) must have a serum pregnancy test 
performed within 7 days prior to registration. A pregnancy test must be done 
within 7 days prior to the first dose as well. Thus, results from the test done prior to 
registration can be used as long as it was not done more than 7 days prior to dosing. 
12. Radiological assessment of tumors: patients must have a chest x-ray, a chest CT, and 
a pelvic/abdominal CT or MRI, as well as a bone scan within 4 weeks of registration 
unless a PET scan has been done. A PET scan is acceptable for screening of organs to 
establish nonmeasurable disease, but is not acceptable to document measurable 
disease. Measurable disease must be established on physical examination or CT scan 
or MRI. Please see RECIST definition of measurable disease (Section 10.1.1). The 
methods used for prestudy assessments (CT, MRI, or PET) should be used throughout 
the study. If possible, the same equipment should be used each time. Under RECIST 
criteria, PET cannot be used to assess measurable disease.  

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13. Assessment of HER2 status will be conducted at the local site using available archival 
breast cancer tissue from each patient and performing a FISH or IHC test. Patients 
will be considered HER2+ if their breast cancers are FISH positive or IHC3+. 
Patients whose breast cancers are HER2 2+ by IHC must undergo FISH testing to 
determine whether their breast cancer is HER2- (negative) or HER2+ (positive). This 
assessment does not have to be repeated if it was performed >3 weeks prior to 
registration. 
14. Paraffin-embedded breast cancer tissue (either paraffin blocks or 20 unstained slides) 
must be available for analysis of EGFR, cytokeratin, and other biological markers. 
These samples will be sent to the Molecular Profiling Institute (MPI; see Appendix 
VII).  
8.2 
ASSESSMENTS DURING TREATMENT 
The following evaluations will be performed during therapy (up to 3 days prior to the 
beginning of each cycle). Any delay within this window is NOT a deviation:  
1. A brief physical examination, including vital signs and body weight (calculation of 
BSA). Doses will be recalculated only in cases of weight changes >10%. 
2. Brief medical history 
3. Review of concomitant medications, prior to Cycle 1 dosing only 
4. A CBC with differential and platelet count 
5. A CMP 
6. Assessment of magnesium 
Note: Careful monitoring of magnesium is necessary to avoid magnesium-wasting 
syndrome that has been reported in patients receiving cetuximab in combination 
with irinotecan and carboplatin. 
7. Calculation of ClCr using the Cockcroft-Gault formula (Appendix III)  
Note: Do not recalculate the carboplatin dose based on increases or decreases in 
ClCr of <20%. 
8. Tumor response by clinical assessment of the patient’s disease (ie, by physical 
examination) must be performed at the beginning of each cycle of therapy  
9. Radiological assessment of tumors to follow known disease will be performed every 
6 weeks for 6 months and then every 12 weeks thereafter. Bone scans will be 
repeated every 16 weeks. The methods used for prestudy assessments (CT, MRI, or 
PET) should be used throughout the study. If possible, the same equipment should be 
used each time. Under RECIST criteria, PET cannot be used to assess 
measurable disease. 
10. Assessments of other sites of disease must be performed only to confirm a CR.  

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11. Paraffin-embedded breast cancer tissue (either paraffin blocks or 20 unstained slides, 
must be available for analysis of EGFR, cytokeratin, and other biological markers. 
These samples will be sent to the Molecular Profiling Institute (MPI; see Appendix 
VII). 
12. A toxicity assessment must be performed.  
Note: Specific grading of alopecia will be documented on the eCRF.  
13. Review of concomitant medications prior to Cycle 1. 
8.3 
OFF TREATMENT ASSESSMENTS 
This is a single assessment that will be performed when patient finishes treatment (off 
treatment because of PD or toxicity). Note that Arm 1 patients who progress on ICb or 
Arm 1 patients who stopped taking ICb for toxicity who progress, provided that they did 
not receive any intervening nonprotocol therapy, will cross over to treatment with single-
agent Erbitux on the Arm 2 treatment schema until disease progression.  
The following evaluations will be performed, within 7 days (unless otherwise specified), 
following the last treatment: 
1. A complete physical examination, including vital signs, and body weight  
2. Assessment of PS on the ECOG scale (Appendix I)  
3. A CBC with differential and platelet count 
4. A CMP  
5. A tumor clinical assessment of the patient’s disease (ie, by physical examination) 
6. Radiological assessment of tumors follow known disease. The methods used for 
prestudy assessments (CT, MRI, or PET) should be used throughout the study. If 
possible, the same equipment should be used each time. Under RECIST criteria, PET 
should not be used to assess measurable disease.  
7. Date and site of relapse or progression (for patients who go off due to PD) 
8. A toxicity assessment  
9. Survival status 
10. If not already done on study, paraffin blocks or slides for the assessment of 
biomarkers to predict whether or not the patient will benefit from Erbitux, will be 
shipped to MPI (see Appendix VII).  
8.4 
FOLLOW-UP ASSESSMENTS 
Patients will participate in this study until their disease progresses. Follow-ups will be 
performed every 3 months from the date of last treatment dose. 

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8.4.1 
Treatment Failure Follow-up 
Patients who discontinue treatment (for reasons outlined in Section 4.4) will be 
followed every 3 months until disease progression for the following information.  
1. Subsequent therapy given following this study therapy  
2. Date and site of relapse or progression  
3. Survival status  
4. Toxicities will be recorded for the first 30 days following the last study treatment 
(specific grading of alopecia is to be documented on the eCRF). 
5. If not already done on study, at first follow-up visit only, ensure that paraffin blocks 
or slides for the assessment of biomarkers, to predict whether or not the patient will 
benefit from Erbitux, will be shipped to MPI (see 8.3 #10). 
This information will be documented on the eCRF within 15 days of the patient’s visit. 
8.4.2 
Response Follow-Up  
For patients with a CR, PR, or SD who are no longer receiving study treatment due 
to toxicity or patient choice, the following assessments will be performed approximately 
every 3 months (unless stated otherwise) until disease progression.  
1. Brief medical history 
2. A physical examination including vital signs, and body weight 
3. CBC with differential and platelet count 
4. A CMP 
5. A tumor clinical assessment of the patient’s disease (ie, by physical examination) and 
a CT scan of known areas of disease (patients will be imaged every 3 months until 
progressive disease). 
6. Date and site of relapse or progression 
7. Toxicities will be recorded for the first 30 days following the last study treatment  
8. Survival status 
9. If not already done on study, at first follow-up visit only, ensure that paraffin blocks 
or slides for the assessment of biomarkers, to predict whether or not the patient will 
benefit from Erbitux, will be shipped to MPI (see 8.3 #10). 
Note: Patients who experience PD after having a CR, PR, or SD, will be followed as 
described in Treatment Failure Follow-up (Section 8.4.1). Patients who die or withdraw 
consent are considered off study and no further information will be collected.  

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9 SAFETY EVALUATIONS 
9.1 
ADVERSE EVENTS 
All Grade 2, 3, and 4 nonhematological adverse events (AEs), Grades 1 and 2 alopecia, 
and Grade 2, 3, and 4 hematologic toxicities will be recorded in the eCRF throughout the 
trial. In addition, all treatment-related Grade 1 and 2 laboratory abnormalities, which are 
deemed “clinically significant” by the Treating Physician, will be documented in the 
eCRF. 
Adverse events (AEs) will be recorded throughout the trial. Toxicities and AEs will be 
graded and reported using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 as linked in Appendix VI. The relationship of each event to 
treatment will be assessed by the Treating Physician and recorded on the eCRF. 
Additional information about each event, such as treatment required, eventual outcome, 
and whether or not therapy had to be interrupted or dosages reduced, will also be 
recorded on the eCRF. Adverse events will be recorded for up to 30 days following the 
last study treatment. 
Definitions and additional reporting instructions are provided in Part II of this protocol. 
9.2 
LABORATORY DATA 
For the treatment of the patient, laboratory data will be obtained according to the 
schedule of assessments. Only the laboratory data requested on the eCRF need to be 
recorded on the appropriate laboratory eCRF page. In addition, abnormal results that are 
associated with an AE will be documented on the Adverse Event page of the eCRF if the 
laboratory abnormality fits the definition of an AE or can potentially result in an AE. 
10 
EFFICACY ASSESSMENTS 
10.1 DEFINITIONS 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee.31 Changes in only the largest diameter (unidimensional measurement) of the 
tumor lesions are used in the RECIST criteria. Best response will be determined based on 
the sequence of disease status with corresponding best response (Appendix IV). 
Note: Lesions are either measurable or non-measurable using the criteria provided below. 
The term “evaluable” in reference to measurability will not be used because it does not 
provide additional meaning or accuracy. 

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10.1.1 Measurable Disease 
Lesions that can be accurately measured in at least 1 dimension (longest diameter to be 
recorded) as ≥ 20 mm with conventional techniques (CT, MRI, X-ray) or as ≥10 mm with 
spiral CT scan.  
Note: PET cannot provide accurate measurements and cannot be used for repeated 
measurements throughout the study. RECIST does not include measurements by PET. 
10.1.2 Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan) are considered 
nonmeasurable disease. Lesions that are considered as truly nonmeasurable include the 
following: 
1. bone lesions 
2. leptomeningeal disease 
3. ascites 
4. pleural/pericardial effusion 
5. inflammatory breast disease 
6. lymphangitis cutis/pulmonis 
7. abdominal masses that are not measurable on imaging techniques  
8. cystic lesions 
10.2 TUMOR RESPONSE EVALUATION 
10.2.1 Evaluation of Lesions 
10.2.1.1 Target Lesions 
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repetitive 
measurements (either by imaging techniques or clinically). A sum of the longest diameter 
for all target lesions will be calculated and reported as the baseline sum longest diameter 
(LD). The baseline sum of the LD will be used as reference to further characterize the 
objective tumor response of the measurable dimension of the disease. 
10.2.1.2 Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, and 
these lesions should be followed as “present” or “absent.” 

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10.3 RESPONSE CRITERIA 
10.3.1 Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. 
• Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions taking as reference the baseline sum LD. 
• Progression (PD): At least a 20% increase in the sum of LD of target lesions taking 
as reference the smallest sum LD recorded since the treatment started or the 
appearance of 1 or more new lesions. 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum LD since the treatment 
started. 
10.3.2 Evaluation of Non-Target Lesions 
• Complete Response: Disappearance of all non-target lesions and normalization of 
tumor marker level. 
• Incomplete Response/Stable Disease: Persistence of 1 or more non-target lesions 
(non-CR) and/or maintenance of tumor marker level above the normal limits. 
• Progressive Disease: Appearance of 1 or more new lesions. Unequivocal progression 
of existing non-target lesions. Although a clear progression of “non-target” lesions 
only is exceptional, in such circumstances, the opinion of the Treating Physician 
should prevail, and the progression status should be confirmed at a later time by the 
review panel (or study chair). 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 

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10.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient’s best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria (see section Evaluation of Target Lesions). See Appendix IV for sequence of 
disease status with corresponding best response. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration”. Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
10.4 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations will be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
Note: Tumor lesions that are situated in a previously irradiated area may or may not be 
considered measurable disease.  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of treatment. 
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (eg, skin nodules, palpable lymph nodes). In the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. 
Table 12. Evaluation of Best Overall Response

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Chest X-rays: Lesions on chest X-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: These techniques should be performed with cuts of 10 mm 
or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen, and 
pelvis. Head & neck tumors and those of extremities usually require specific protocols. 
Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules. Ultrasound may also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific additional criteria for standardized usage of 
prostate-specific antigen (PSA) and CA-125 response in support of clinical trials are 
being developed. 
10.5 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
10.5.1 Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed. In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that will be performed not less than 4 weeks after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD 
criteria (Section 10.3.1), at least once after study entry at a minimum interval (not less 
than 6 weeks).  
10.5.2 Duration of Response 
The duration of overall response is measured from the first date measurement criteria are 
met for CR/PR (whichever status is recorded first) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started), or last date of 
follow-up for patients who do not progress. 
The duration of overall complete response is measured from the date measurement 
criteria are first met for CR until the first date that recurrent disease is objectively 
documented. If a patient has not progressed or died, duration of response is censored at 
the date of last follow-up. 

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10.5.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met and considering that the duration of stable disease is at least 6 weeks 
(2 cycles) from the start of treatment. If a patient has not progressed or died, duration of 
response is censored at the date of last follow-up. 
10.6 PROGRESSION-FREE SURVIVAL 
Progression-free survival will be measured from the treatment start date (date of first 
dose) to either the date the patient is first recorded as having disease progression (even if 
the patient went off treatment because of toxicity) as long as the patient does not start a 
new treatment, or the date of death if the patient dies due to any causes before 
progression. Patients who start a new treatment before they progress will be censored as 
of the date of start of the new treatment. If a patient has not progressed or died, time to 
progression is censored at the date of last follow-up. 
10.7 TIME TO PROGRESSION 
For patients who progress, time to progression (TTP) will be measured from the 
treatment start date (date of first dose) to the date the patient is first recorded as having 
disease progression (even if the patient went off treatment because of toxicity). Patients 
who start a new treatment before they progress will be censored as of the date of start of 
the new treatment. 
10.8 SURVIVAL 
Survival will be measured from the date of start of treatment to the date of death. For 
patients who do not die, survival will be censored at the date of the last follow-up. 
10.9 TIME TO RESPONSE 
For patients who achieve an objective response (CR or PR of measurable disease), the 
time to response will be assessed from the date of start of treatment to the date of first 
response. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 
PATIENT POPULATIONS 
11.1.1 Efficacy Analysis 
For the tumor response analysis, 3 patient populations will be defined: all eligible 
patients, evaluable patients, and patients who received study drugs. 
Intent-to-treat Population 
This population includes all eligible patients registered on study regardless of whether or 
not patients received any study drug. 
Efficacy, Evaluable Population (Per-protocol Population) 
Evaluable patients include all patients who received at least 2 cycles of treatment with at 
least 1 follow-up tumor assessment. If progressive disease occurs before 2 cycles can be 
administered, the patient will be considered PD. If lethal toxicity or discontinuation of 
treatment secondary to toxicity occurs, the patient will be considered a treatment failure.  
Safety Analyses 
The safety analysis will include all eligible patients who are registered on the study and 
who received at least 1 dose of any study drug. Adverse events that are unrelated to 
treatment and occur >30 days after the administration of treatment will not be reported or 
analyzed. 
11.2 OBJECTIVES AND ENDPOINTS 
The primary objective of this study is to determine the overall response rate when Erbitux 
is added to ICb in patients with metastatic breast cancer. Secondary objectives are: 
• To calculate the duration of response and stable disease 
• To determine the median progression-free survival (PFS) and time to progression 
(TTP – only for those who progress)  
• To determine the median overall survival (OS)  
• To determine toxicities for individuals with metastatic breast cancer treated with 
these study regimens 
• To determine EGFR expression for individuals with metastatic breast cancer enrolled 
on this study 

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11.3 SAMPLE SIZE 
124 patients will undergo a 1:1 randomization to ICb + Erbitux versus ICb alone 
followed by Erbitux at progression. Patients in each group will be stratified by hormone 
receptor negative and HER2 negative breast cancer (triple negative) until a cohort of 
24 patients are registered in each arm. This is a noncomparative study; no direct 
statistical comparisons will be made between the 2 groups. The 2 groups will run parallel 
to each other. Using STPlan exact method, a total of 62 patients in each group (including 
10% for early dropouts) will provide 80% power with a type I error rate of 5% to reject 
the null hypothesis that the ORR is less than 60% (approximately 37 response) in the ICb 
+ Erbitux group (Ho = 0.43), and less than 43% (approximately 27 response) in the ICb 
alone group (Ho = 0.27). On an estimated accrual of 8 patients per month, the anticipated 
time to accrual is 16 months. Patients will be followed until disease progression or death 
(if death occurs prior to progression).  
Thirty more patients will be added to the study for a total of 154 patients (from the 
original sample size of 124 patients). The reason for increasing the sample size 
(15 additional patients in each arm) is to replace the nonevaluable patients who went off-
treatment early due to adverse events or withdrawal of consent. 
A final report could be generated when all patients complete treatment and have been 
followed for at least 2 years. 
11.4 STATISTICAL METHODS 
Patient characteristics including race, sex, ECOG performance status, prior treatment(s) 
and age will be evaluated using descriptive statistics for each group in the ITT 
population. In the evaluable population, the objective response rates, together with the 
95% confidence interval will be determined, as well as the duration of response. The 
median and range of cycles received per arm and for the crossover will be listed. The  
1- and 2-year progression-free survival and survival will be analyzed using the Kaplan-
Meier survival method.32 For patients who progressed, median time to progression and 
ranges will be presented. Reasons off treatment and causes of death will be reported.  
The number of patients who crossed over in Arm 1 will be listed as well as their 
responses to Erbitux following the crossover. 
Incidence and type of adverse events will be tabulated and summarized using descriptive 
statistics. Toxicities will be graded and reported according to the NCI CTCAE version 
3.0. The toxicity profile of the study drugs will be evaluated in the safety population. 
Patients who receive at least 1 dose of any study drug will be included in the safety 
analysis. 

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PART II – PROCEDURES 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
BMS considers the SAE reporting period to begin with signing of the informed 
consent. 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious. This also applies to patients experiencing AEs that cause interruption or 
discontinuation of investigational product, or those experiencing AEs that are present at 
the end of their participation in the study. Such patients should receive post-treatment 
follow-up as appropriate. If an ongoing AE changes in its severity or in its perceived 
relationship to study drug, a new AE entry for the event should be completed. 
12.1 DEFINITIONS 
12.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
12.1.2 Serious Adverse Event 
An AE (experience) or reaction occurring at any dose should be classified as a serious 
adverse event (SAE) if any of the following occur: 
Death: Any death from any cause while a patient is receiving treatment on this protocol, 
or ≤30 days following the last dose of protocol treatment, must be reported to the SI (Dr. 
Joyce O’Shaughnessy, 214-370-1796), Bristol-Myers Squibb and to the IRB within 24 
hours of first notification. A serious AE is any untoward medical occurrence that at any 
dose:  
• results in death,  
• is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe),  
• requires inpatient hospitalization or causes prolongation of existing hospitalization,  
• results in persistent or significant disability/incapacity,  
• is a congenital anomaly/birth defect,  

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• results in the development of drug dependency or drug abuse,  
• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (eg, medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) 
For reporting purposes, BMS also considers the occurrences of pregnancy or 
overdose (regardless of adverse outcome) as events, which must be reported as 
important medical events. 
Adverse events classified as “serious” require expeditious handling and reporting to BMS 
to comply with regulatory requirements.  
All serious AEs whether related or unrelated to investigational product, must be 
immediately reported to BMS (or designee) by confirmed facsimile transmission. If only 
limited information is initially available, follow-up reports are required. The original 
SAE form must be kept on file at the study site. 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the FDA as soon as possible and, in no event, later than 
7 days (death or life-threatening event) or 15 days (all other SAEs) after the 
Investigator’s or institution’s initial receipt of the information. Bristol-Myers Squibb will 
be provided with a simultaneous copy via facsimile of all adverse events filed with the 
FDA. SAEs should be reported on the MedWatch Form 3500A, which can be accessed 
at: 
http://www.accessdata.fda.gov/scripts/MedWatch/ 
MedWatch forms should be sent to the FDA online at the above Internet address or at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
All SAEs should simultaneously be faxed to Bristol-Myers Squibb at: 
Global Pharmacovigilance 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Collection of complete information concerning SAEs is extremely important. Thus, 
follow-up information which becomes available as the SAE evolves, as well as 
supporting documentation (eg, hospital discharge summaries and autopsy reports), should 

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be collected subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
12.1.3 Unexpected Adverse Event 
An unexpected event is any AE that is not identified in nature, severity or frequency in 
the Clinical Investigator’s brochure or the drug package insert. 
12.2 REPORTING 
12.2.1 Adverse Events 
Adverse events will be recorded for the duration of a patient’s study treatment, and for up 
to 30 days following the last study treatment. All AEs, regardless of causal relationship 
are to be recorded in the source documentation. Only those specified in Section 9.1 are to 
be recorded in the eCRF.  
The Treating Physician must determine and record the toxicity of AEs. Toxicities will be 
graded and reported according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 3.0 as linked in Appendix VI. The relationship of each event to 
treatment will be assessed by the Treating Physician and recorded on the eCRF. 
Additional information about each event, such as treatment required, whether or not 
therapy had to be interrupted or dosages reduced, and eventual outcome will also be 
recorded on the eCRF. 
Pre-existing conditions will be recorded at baseline on the Medical History Form. If a 
pre-existing condition does not change, it does not have to be reported as an AE on 
subsequent cycles. 
12.2.2 Serious Adverse Events  
All SAEs will be reported by telephone upon becoming aware of the event to US 
Oncology Central Safety Department. The SAEs should be reported by facsimile within 
24 hours to Bristol-Myers Squibb and to the US Oncology Central Safety Department. A 
copy will be sent to the FDA (if applicable) by US Oncology Central Safety Department. 
A facsimile cover page will be available with both Bristol-Myers Squibb and US 
Oncology Central Safety Department contact information.  
US Oncology Central Safety Department 
Regulatory Affairs - Safety 
 
US Oncology, Inc. 
4144 N. Central Expwy 
Suite 1250 
Dallas, TX 75204 
Direct: (214)-584-3205 
Fax: (214) 584-3403 
Toll Free Fax: 1-877-571-8934 
The site will supply as much information as available at the time of the initial fax to 
Bristol-Myers Squibb and to the US Oncology Central Safety Department (study number, 

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subject initials, subject study number, event), during both business and non-business 
hours, to: 
Sponsor contact information –  
Global Pharmacovigilance and Labeling 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
 
All SAEs must be documented on the Serious Adverse Event Report Form and on the 
adverse event eCRF page. The event term used on the SAE report should match the term 
in the eCRF. The Coordinators should fax the completed Forms to Bristol-Myers Squibb 
and to the USOR Central Safety Department (see contact information below) within 
24 hours of becoming aware of the event. This fax will serve as the initial report. The 
USOR Central Safety Department will forward the necessary information to the Study 
Investigator, the Institutional Review Board (via notification letter), FDA (if applicable) 
and the data fax line (Dallas or Houston). 
Questions and concerns from the above regarding the SAE Report will be addressed 
directly from Bristol-Myers Squibb, who will subsequently contact the site for 
answers/clarification. Any follow-up/final information from the Coordinator will be 
faxed directly to Bristol-Myers Squibb. In addition this follow-up/final report will need to 
the faxed to the USOR Central Safety Department to continue with the procedure 
outlined above.  
In the instance where a participating site utilizes a local IRB, the Treating Physician or 
designee will be held responsible for notification of the serious adverse event to their 
local IR. 
12.2.3 Overdose 
An overdose is defined as the accidental or intentional ingestion of any dose of a product 
that is considered both excessive and medically important. For reporting purposes, BMS 
considers an overdose, regardless of adverse outcome, as an important medical event (see 
Serious Adverse Events). 
12.2.4 Discontinuation of Patient 
The Treating Physician must notify the SI at any time following discontinuation of a 
patient on study for the occurrence of a serious or unexpected AE associated with the use 
of the study medication. 
12.3 PREGNANCY 
Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of 
the importance of avoiding pregnancy during trial participation and the potential risk 
SAEs MUST BE SENT TO 
(Bristol-Myers Squibb) and to the 
US Oncology Central Safety 
Department by fax within 24 hours 
of notification by the site. 

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factors for an unintentional pregnancy. In addition, men enrolled on this study should 
understand the risks to any sexual partner of childbearing potential and should practice an 
effective method of birth control. 
All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving 
investigational product. If the pregnancy test is positive, the patient must not receive 
investigational product and must not be enrolled in the study. 
In addition, all WOCBP should be instructed to contact the Investigator 
immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period) at any time during study participation. 
The Investigator must immediately notify BMS in the event of a confirmed pregnancy in 
a patient participating in the study. 
13 
PROTOCOL AND DATA DEVELOPMENT 
13.1 ETHICS 
13.1.1 Institutional Review Board 
This trial can be undertaken only after review and full approval of the protocol and a 
Patient Informed Consent Form has been obtained from a properly constituted IRB. This 
written approval must be dated and it must clearly identify the protocol, any amendments, 
the Patient Informed Consent Form, and any applicable recruiting materials and subject 
compensation programs approved. 
The decision concerning the conduct of the study will be made in writing to the SI. 
Copies of this decision and of all IRB correspondence will be kept on file at the study 
site; copies will be provided to the USOR Research Office. 
During the trial, the SI is required to send various documents to the IRB for review: 
1. Changes to the current protocol. 
2. All protocol amendments and Patient Informed Consent Form revisions. 
3. Reports of AEs that are serious, unexpected, and associated with the investigational 
drug, and any life-threatening problems, or death. 
4. Required progress reports. 
If local IRB approval is acquired, the USOR Regulatory Affairs Office should be 
informed via research Standard Operation Procedures (SOP). 
Particular attention is drawn to the FDA regulations regarding the IRB. The SI provides 
Bristol-Myers Squibb and Pfizer, Inc. with the necessary assurance that an IRB is 
responsible for the initial and continuing review and approval of the proposed clinical 

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study in accordance with these regulations. At least once a year, the IRB will be asked to 
review and re-approve the clinical trial protocol; the request must be documented in 
writing. At the end of the trial, the SI will notify the IRB that the trial has been 
completed. 
13.1.2 Patient Informed Consent 
The informed consent should meet the requirements of the latest version of the 
Declaration of Helsinki and any applicable regulations and guidelines. It must be 
approved by an institutional ethics committee/IRB. 
Prior to entry into the trial and before any protocol-required procedures are performed, 
the Treating Physician must explain the nature of the trial, its intended purpose, and the 
implications of participation to potential patients or to their legal representatives. They 
will be told about the possible risks and benefits, and the possible adverse experiences. 
They will be informed that patients’ participation is voluntary, and that they may 
withdraw consent to participate at any time. They will also be informed that if patients 
choose not to participate in the trial alternative treatments are available; such refusal will 
not prejudice further treatment of their disease. Potential patients or their legal 
representatives must be given the opportunity to ask questions about the trial protocol and 
the procedures involved. 
Finally, each patient will be told that his or her records may be accessed by authorized 
personnel of USOR and other authorized individuals without violating the patient’s 
confidentiality, to the extent permitted by the applicable laws and/or regulations. By 
signing the written Patient Informed Consent Form, the patient or his or her legal 
representative is authorizing such access. Following this explanation and prior to entry 
into the trial, the written, dated, and signed Patient Informed Consent Form must be 
obtained from each patient or his or her legal representative; a copy will be given to the 
person signing the form. 
13.1.3 Confidentiality of Records 
The Treating Physician is required to retain, in a confidential manner, sufficient 
information on each patient (ie, full name, current address, and social security number) so 
that the patient may be contacted by the FDA or by the USOR should the need arise. 
13.2 STUDY RECORDS 
13.2.1 Documentation 
A log of all patients evaluated for this protocol must be maintained at each site. Patients 
excluded from admission will be provided with a clear explanation of the specific reasons 
why they have been excluded from the study. Patients who are included will be assigned 
a patient identification number. 
For each patient treated with the study drug(s), the Research Coordinator is required to 
prepare and maintain case histories that include all observations and other data pertinent 

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to the investigation. This will include all source documents needed to verify the accuracy 
of all observations and other data contained in the eCRFs on each study patient. 
The Treating Physician or his/her designee is required to retain the records related to the 
trial for a period of 2 years following the date a marketing application is approved for the 
indication being investigated. If no application is to be filed or if the application is not 
approved for such indication, the records must be retained until 2 years after the 
investigation is discontinued and the regulatory agencies are notified. 
The Treating Physician shall retain study drug disposition records, copies of eCRFs (or 
electronic files), and source documents for the maximum period required by the country 
and institution in which the study will be conducted, or for the period specified by 
USOR, whichever is longer. The Investigator must contact USOR prior to destroying any 
records associated with the study. 
If the Investigator withdraws from the study (eg, relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (eg, another Investigator, IRB). Notice 
of such transfer will be given in writing to USOR. 
13.2.2 Electronic Case Report Form Procedures 
Data will be entered at the site using eCRFs. The Treating Physician or his/her designee 
is responsible for recording all data relating to the trial on the eCRFs. The Treating 
Physician must verify that all data entries on the eCRFs are accurate and correct eCRFs 
must be completed within 15 days of the end of each cycle following the completion of 
study therapy. 
If an item is not available or is not applicable, it should be documented as such; no blank 
spaces should be left on an eCRF. 
For patients removed from study, the Clinical Research Office Project Manager must be 
notified by e-mail within 3 working days of the removal. eCRFs must then be completed 
within 15 days of the date of removal from the study. Long-term survival information 
will be collected. 
13.3 MONITORING/SITE VISITS 
Study sites will be monitored through regular site visits conducted at least once per year 
by the regional quality and compliance auditor of USOR. To ensure accuracy, a minimal 
data set from the eCRFs for all cases will be compared with the original patient source 
documents during site visits. The monitor may also review case histories, laboratory 
certifications, IRB records, drug accountability records, and other documentation. In 
addition, representatives of the FDA or of other regulatory agencies may review study 
records. 
At all times, patients’ confidentiality will be monitored. 

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13.4 MODIFICATION OF PROTOCOL 
Any changes to this protocol that affect study objectives, study design, study procedures, 
patient population, or significant administrative procedures will require a formal 
amendment to the protocol. Any proposed protocol amendments must be sent in writing 
to the applicable IRB. Prior to implementation, an amendment must be agreed upon by 
the SI, Bristol-Myers Squibb, and Pfizer, Inc., and approved by the applicable IRB. 
General administrative changes to the protocol are minor corrections and/or clarifications 
that do not affect the manner in which the study is to be conducted. Such administrative 
changes will be agreed upon by the SI and will be documented in a memorandum. The 
applicable IRB will be notified of administrative changes according to applicable IRB 
guidelines.

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2. Adjuvant Therapy for Breast Cancer: NIH Consensus Statement Online 2000. 
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3. FDA Oncology Tools Approval Summary for irinotecan for Accel. Approv. (clinical 
benefit subsequently established) Treatment of patients with metastatic carcinoma of 
the colon or rectum whose disease has recurred or progressed following 5-FU-based 
therapy. Available at: 
http://www.accessdata.fda.gov/scripts/cder/onctools/summary.cfm?ID=158 . 
Accessed on January 20, 2005. 
4. Slichenmyer WJ, Von Hoff DD. New natural products in cancer chemotherapy. J 
Clin Pharmacol. 1990;30:770-88. 
5. Chen AY, Yu C, Potmesil M, et al. Camptothecin overcomes MDR1-mediated 
resistance in human KB carcinoma cells. Cancer Res. 1991;51:6039-6044. 
6. Pommier Y, Leteurtre F, Fesen MR, et al. Cellular determinants of sensitivity and 
resistance to DNA topoisomerase inhibitors. Cancer Invest. 1994;12:530-542. 
7. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of 
cisplatin and carboplatin. J Clin Oncol 1999;17:409-22 
8. McEvoy GK, ed. AHFS 2000 Drug Information. Bethesda, Maryland: American 
Society of Health-System Pharmacists, Inc.; 2000. 
9. Atagi S, Kawahara M, Ogawara M, et al. Phase II trial of daily low-dose carboplatin 
and thoracic radiotherapy in elderly patients with locally advanced non-small cell 
lung cancer. Jpn J Clin Oncol 2000;30:59-64 
10. Groen HJ, van der Leest AH, de Vries EG, et al. Continuous carboplatin infusion 
during 6 weeks’ radiotherapy in locally inoperable non-small-cell lung cancer: a 
phase I and pharmacokinetic study. Br J Cancer 1995;72:992-997. 
11. Kolaric K, Vukas D. Carboplatin activity in untreated metastatic breast cancer 
patients--results of a phase II study.Kaplan EL, Meier P. Nonparametric estimation 
from incomplete observations. JASA. 1958;53:457-481. 
12. Martin M, Diaz-Rubio E, Casado A, Santabarbara P, Lopez Vega JM, Adrover E, 
Lenaz L. Carboplatin: an active drug in metastatic breast cancer. J Clin Oncol. 1992 
Mar;10:433-437. 
13. Robert N, et al, 2005, Personal communication. 
13a.Wild CA, Wang S, Gandera DR, et al. Determination of population-based maximum 
tolerated dose: phase I trila of irinotecan and carboplatin in solid tumors [abstract 
2116]. Proc Am Soc Clin Oncol. 2002;21:76b. 
14. Fukuda M, Oka M, Soda H, Kinoshita A. Phase II study of irinotecan combined with 
carboplatin in previously untreated non-small-cell lung cancer. Cancer Chemother 
Pharmacol. 2004 Dec;54:573-577. 

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14a. Okubo S, Kurebayashi J, Sonoo H, et al. Retrospective study on utility of irinotecan 
hydrochloride in patients with advanced and recurrent breast cancer. Gan To 
Kagaku Ryoho. 2003; 20:1441. 
14b. Perez EA, Hillman DW, Mailliard JA, et al. Randomized phase II study of two 
irinotecan schedules for patients with metastatic breast cancer refractory to an 
anthracyclines, a taxane, or both. J Clin Oncol. 2004; 22:2849. 
15. Mendelsohn J, Baird A, Fan Z, Markowitz SD: Growth factors and their receptors in 
epithelial malignancies, in Mendelsohn J, Howley PM, Israel MA, Liotta LA (eds): 
The Molecular Basis of Cancer. Philadelphia, PA, W.B. Saunders Company, 2001, pp 
137-144.  
16. Huang SM, Harari PM: Epidermal growth factor receptor inhibition in cancer 
therapy: biology, rationale and preliminary clinical results. Invest New Drugs 
1999;17:259-269. 
17. Tzahar E, Waterman H, Chen X, et al: A hierarchical network of interreceptor 
interactions determines signal transduction by Neu differentiation factor/neuregulin 
and epidermal growth factor. Mol Cell Biol 1996;16:5276-5287. 
18. Lenferink AE, Pinkas-Kramarski R, van de Poll ML, et al: Differential endocytic 
routing of homo-and hetero-dimeric erb B tyrosine kinases confers signaling 
superiority to receptor heterodimers. EMBOJ 1998;17:3385-3397. 
19. Karunagaran D, Tzahar E, Beerli RR, et al: Erb B-2 is a common auxiliary subunit of 
NDF and EGF receptors: implications for breast cancer. EMBO J 1996;15:254-264. 
20. Chou JL, Fan Z, DeBlasio T, Koff A, Rosen N, Mendelsohn J. Constitutive 
overexpression of cyclin D1 in human breast epithelial cells does not prevent G1 
arrest induced by deprivation of epidermal growth factor. Breast Cancer Res Treat. 
1999;55:267-283. 
21. Fan Z, Shang BY, Lu Y, Chou JL, Mendelsohn J. Reciprocal changes in p27KIP1 and 
p21CIP1 in growth inhibition mediated by blockade or overstimulation of epidermal 
growth factor receptors. Clin Cancer Res. 1997;3:1943-1948. 
22. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an 
anti-epidermal growth factor receptor monoclonal antibody in a human colorectal 
carcinoma cell line and its delay by insulin. J Clin Invest. 1995; 95:1897-1905. 
23. ERBITUX™ (cetuximab) package insert. ImClone Systems Incorporated and Bristol-
Myers Squibb Company. 2004. ER-B0001-02-04. 
24. Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in 
combination with irinotecan (CPT-11) in patients with epidermal growth factor 
receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC) 
[Abstract 1012]. Proc Am Soc Clin Oncol. 2003;22:252. 

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25. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-
11) is active in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal 
growth factor receptor (EGFR) [Abstract 7]. Proc Am Soc Clin Oncol. 2001:20:3a. 
26. Saltz LB, Meropol NJ, Loehrer PJ, et al. Phase II Trial of Cetuximab in Patients with 
Refractory Colorectal Cancer that Expresses the Epidermal Growth Factor Receptor. 
J Clin Oncol. 2004;22:1201-1208. 
27. Perez EA, Hillman DW, Mailliard JA, et al. Randomized phase II study of two 
irinotecan schedules for patients with metastatic breast cancer refractory to an 
anthracycline, a taxane, or both. J Clin Oncol. 2004;22:2849-2855. 
28. Ciardiello F, Bianco R, Damiano V, et al. Antiangiogenic and antitumor activity of 
anti-epidermal growth factor receptor C225 monoclonal antibody in combination with 
vascular endothelial growth factor antisense oligonucleotide in human GEO colon 
cancer cells. Clin Cancer Res. 2000;6:3739-3747. 
29. Ciardiello F, Tortora G. Expert Opin Investig Drugs. 2002;11:755-768. 
30. Eisenhauer EA, Vermorken JB. The taxoids. Comparative clinical pharmacology and 
therapeutic potential. Drugs. 1998;55:5-30. 
30a. Schrag D, Chung KY, Flombaum C, Saltz L. Cetuximab therapy and symptomatic 
hypomagnesemia. J Natl Cancer Inst. 2005;97:1221-1224. 
31. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the 
response to treatment in solid tumors. European Organization for Research and 
Treatment of Cancer, National Cancer Institute of the United States, National Cancer 
Institute of Canada. J Natl Cancer Inst. 2000;92:205-216. 
32. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. JASA. 
1958;53:457-481. 

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Appendix I 
ECOG Performance Status Scale 
Grade  
Description 
0 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of light or sedentary nature—(eg, light 
housework or office work) 
2 
Ambulatory and capable of all self care, but unable to carry out 
any work activities; up and about > 50% of waking hours 
3 
Capable only of limited self-care, confined to bed or chair > 
50% of waking hours 
4 
Completely disabled; cannot carry out any self care; totally 
confined to bed chair 
5 
Dead 
 

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Appendix II Staging 
The sixth edition of The American Joint Committee on Cancer Staging Manual will be 
used to stage breast cancer in order to determine eligibility for this study. This manual 
may be obtained at the following link on the USOR CTMS: 
https://ctms.usoncology.com/Web_Docs/AJCC%20STAGING%20FORMS/25%20Breast.pdf 
 
 

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Appendix III Calculations 
Body Surface Area 
Actual weight will be used to calculate body surface area and study drug doses for all 
patients, including obese patients. 
Note: Computer programs, which utilize height and weight to calculate BSA and/or drug 
dose, are acceptable as long as they do not vary by >5% (±) from the manual dose 
calculation 
 
The following formulas are recommended for the calculation of BSA: 
The DuBois formula for calculating the body surface area (BSA) in squared meters (m2) 
follows: BSA m2= (Weight in kg) 0.425 (Height in cm) 0.725 x 0.007184 
 
Lam et al and Mosteller (Lam RK, et al. NEJM. 1988;318:1130 (letter) and Mosteller 
RD: Simplified calculation of body surface area. NEJM. 1987;317:1098) have published 
the following simplified formulas that can be calculated using a hand-held pocket 
calculator:  
 or 
 
 
Creatinine Clearance 
Creatinine Clearance (ClCr) – Cockcroft and Gault method  
Cockcroft DW, Gault MH. Nephron. 1976;16:31-41 
Note: It is recommended that the ideal or adjusted (non-obese) weight be used, unless you 
are correcting by the BSA comparison/adjustment method.  
Creatinine clearance (mL/min) =  
(140-age in years) × (actual weight in kg) 
(72 × serum creatinine in mg/dL) 
for female patients, multiply the result by 0.85 
Note: do not use the method of Jelliffe for the calculation of creatinine clearance! 

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Appendix IV Sequence of Disease Status with Corresponding 
Best Response  
1st objective status 
2nd objective status 
3rd objective 
status 
Best response 
3-6 week assessment interval: 
 
 
 
Progression 
--- 
--- 
Progression 
Stable, PR, CR, unk 
Progression 
--- 
Progression 
Stable
1 
Stable 
Progression 
Stable 
Stable, unk
1 
PR, CR 
Progression 
Stable 
Stable, unk 
Unknownd 
Progression 
Unknown 
PR
2 
PR 
Progression 
PR 
PR
2 
CR 
Progression 
PR 
PR, CR 
Unknownd 
Progression 
Unknown 
CR
3 
CR 
Progression 
CR 
Unknown
1 
Stable 
Progression 
Stable 
 
 
 
 
> 6 week assessment interval: 
 
 
Progression 
--- 
--- 
Progression 
Stable
1 
Progression 
--- 
Stable 
PR or CR (no 4 week 
confirmation)
 1 
Progression 
--- 
Stable 
PR (4 week confirmation)
2 
Progression 
--- 
PR 
PR
2 
PR 
Progression 
PR 
PR
2 
CR (no 4 week confirmation) Progression 
PR 
CR (4 week confirmation)
3 
Progression 
--- 
CR 
CR
3 
CR 
Progression 
CR 
Unknown
4 
Progression 
--- 
Unknown 
1. 
Best response is the same if these sequences are preceded by the objective statuses of unknown or stable, or if 
unknowns separate the first objective status from the second. 
2. 
Best response is the same if these sequences are preceded by the objective statuses of unknown, stable, or PR, or if 
unknowns separate the first objective status from the second. 
3. 
Best response is the same if these sequences are preceded by the objective statuses of unknown, stable, PR, or CR, 
or if unknowns separate the first CR from the second. 
4. 
Best response is the same if followed by additional unknowns. 

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Appendix V Schedule of Assessments  
Follow-up (see 8.4) 
Every 3 months until PD  
Assessment 
Prestudy 
see 8.1 
During Treatment
(at the beginning of 
each cycle, unless 
otherwise specified)
see 8.2 
Off Study Tx 
(within 7 days 
of last 
treatment) 
see 8.3 
Treatment 
Failure  
Response  
Informed consent 
a 
 
 
 
 
Signed patient authorization 
(HIPAA) 
a 
 
 
 
 
Inclusion/exclusion criteria 
a 
 
 
 
 
Complete physical examination 
w/in 3 weeks prior 
to registration 
(PTR) 
 
a 
 
 
Brief physical exam 
 
a 
 
 
a 
Medical history  
w/in 3 weeks PTR  
 
 
 
 
Brief medical history 
 
a 
a 
 
a 
Review of concomitant meds 
 
Prior to Cycle 1 
 
 
 
ECOG PS Scale 
w/in 3 weeks PTR  
a 
a 
 
 
CBC with differential and 
platelet count 
w/in 3 weeks PTR  
a 
a 
 
a 
Complete metabolic profile 
w/in 3 weeks PTR  
a 
a 
 
a 
Assessment of magnesium 
w/in 3 weeks PTR  
a 
 
 
 
Creatinine Clearance 
w/in 3 weeks PTR  
a 
 
 
 
Pregnancy test 
w/in 7 days PTR 
and w/in 7 days 
prior to Dose 1 
 
 
 
 
Radiological assessment of 
disease 
w/in 4 weeks PTR  
every 6 weeks for 6 
months then every 12 
weeks. Bone Scans 
every 16 weeks 
a 
 
(CT scan 
every 3 mos 
until PD) 
HER2 status 
a 
 
 
 
 
Tumor response by clinical 
assessment 
 
a 
a 
 
a 
Date and site of relapse or 
progression 
 
 
a 
for pts who PD 
a 
a 
Survival status 
 
 
a 
a 
a 
Toxicity assessment (NCI 
CTCAE) 
 
a 
a 
For 30 days 
after last tx 
For 30 days 
after last tx 
Review of concomitant meds 
 
a 
(Prior to cycle 1) 
 
 
 
Samples (paraffin blocks and/or 
tissue slides) 
Availability 
confirmed 
Send to central lab 
(MPI) for EGFR 
testing by the end of 
Cycle 2 
If not already 
done, send to 
MPI for 
biomarkers 
If not already done, at first 
follow-up visit, make sure that 
paraffin blocks or slides have 
been sent to MPI. 
Subsequent therapy given 
following study therapy 
 
 
 
a 
 
Complete metabolic profile includes: serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, 
chloride, potassium, sodium) 

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Appendix VI Terminology Criteria for Adverse Events (CTCAE), 
Version 3.0 
MARCH 31, 2003 Publish Date: December 12, 2003 
 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
(CTCAE) Version 3.0 
 
 
As of April 02, 2003 NCI has introduced version 3.0 of the Common Terminolgoy Criteria for 
Adverse Events. These may be obtained at the following web link 
http://ctep.cancer.gov/reporting/ctc.html or on the USOR CTMS. 
 
DO NOT USE CTC VERSION 2.0 TO GRADE TOXICITIES IN THIS STUDY! 
 
 

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Appendix VII Pathology Submission Procedure 
Investigators must submit: 
• One paraffin block or 20 unstained slides from a representative area of the tumor 
to be used for molecular studies.  
• Surgical Pathology Report  
• Pathology Submission Form 
Ship directly to The Molecular Profiling Institute (address and phone number below). 
The Pathology Submission Form must be completed and submitted even if the patient 
pathology specimens are not available for submission. Please make a copy of the 
Pathology Submission Form and file in the patient study record and submit a copy to 
Houston Data Research. 
Please indicate on the package “Pathology Specimens Enclosed”. 
 
 
 
 
 
 
 
ADDRESS AND PHONE NUMBER 
The Molecular Profiling Institute 
445 N. Fifth Street 
Phoenix, AZ 85004 
(602) 358-8900