FOLFIRI or FOLFOX With or Without Cetuximab in Patients With Metastatic Adenocarcinoma of the Colon or Rectum

CALGB 80203 was activated on December 15, 2003. In February 2004, based on the results of the
randomized trial of IFL +/- cetuximab showing a significant improvement in overall survival
with cetuximab, cetuximab was approved by the FDA for use as front-line therapy for patients
with metastatic colon cancer. In response to this action, the Data Safety and Monitoring
Board recommended closure of CALGB 80203. CALGB 80203 was subsequently closed to accrual in
January 2005 with 238 of the originally targeted 2200 patients enrolled. A final decision was
to "replace" CALGB 80203 with a three-treatment arm randomized trial of chemotherapy (FOLFOX
or FOLFIRI) with and without cetuximab and/or bevacizumab. The protocol was amended to allow
analysis of the data from CALGB 80203 as a randomized phase II trial and reporting of the
results.

Patients were stratified according to prior adjuvant chemotherapy (yes vs no) and prior
pelvic radiation (yes vs no). Patients must have completed any major surgery or radiotherapy
(eg, chest or bone palliative RT or pelvic RT) ≥ 4 weeks from registration and completed any
minor surgery ≥ 2 weeks from registration. Patients must have fully recovered from the
procedure and/or radiotherapy. Patients must have initiated treatment within 7 days of
registration. Patients were randomized to 1 of 4 treatment arms, please see a description of
the treatment regimens in the "Arms" section. In addition, patients received concomitant and
supportive therapy as appropriate per the protocol.

OBJECTIVES:

Primary

1. To determine if the addition of C225 to FOLFIRI or FOLFOX chemotherapy prolongs survival
of patients with untreated, advanced or metastatic colorectal cancer.

Secondary

1. To determine if the FOLFIRI and FOLFOX regimens are equivalent in terms of survival as
front-line therapy for advanced colorectal patients.

2. To determine the level of EGFR expression in patients with metastatic colorectal cancer.

Patients were followed up to 3 years post-treatment.

1. Locally Advanced or Metastatic Colorectal Cancer

- Eligible patients must have histologically or cytologically documented locally
advanced or metastatic colorectal cancer. The site of the primary lesion must be
or have been confirmed endoscopically, surgically or radiologically to have been
in the large bowel.

- Patients with a history of colorectal cancer treatment by surgical resection who
develop radiological or clinical evidence of metastatic cancer do not require
separate histological or cytological confirmation of metastatic disease unless:

- Either an interval of greater than five years has elapsed between the
primary surgery and the development of metastatic disease OR

- The primary cancer was stage I.

- Clinicians should consider biopsy of lesions to establish the diagnosis of
metastatic colorectal cancer in each case if there is substantial clinical
ambiguity regarding the nature or source of apparent metastases.

2. No prior treatment for advanced or metastatic colorectal cancer

- Patients may have received prior adjuvant chemotherapy (no more than 6 months or
4 cycles) or radiation with radiosensitizing chemotherapy. The last course of
chemotherapy must have concluded > 12 months prior to registration. Patients may
not have previously received irinotecan ≤ or oxaliplatin therapy in either the
adjuvant or metastatic setting. No concurrent use of additional investigational
agents is allowed while participating in this study.

3. Patients may not have had prior radiotherapy to greater than 25% of bone marrow.

Standard adjuvant rectal cancer chemoradiation will not exclude the patient from
protocol entry. Radiation must have concluded ≥ 4 weeks from registration.

4. Patients should have completed any major surgery ≥ 4 weeks from registration. Patients
must have completed any minor surgery ≥ 2 weeks from registration. Patients must have
fully recovered from the procedure. Insertion of a vascular access device is not
considered major or minor surgery.

5. No previous or concurrent malignancy is allowed except for adequately treated basal
cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which
the patient has been disease-free for five years.

6. Age ≥ 18 years

7. CTC (ECOG) performance status of 0-1.

8. No evidence of Gilbert's syndrome - Patients with Gilbert's Syndrome may have a
greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38.
Evidence of Gilbert's Syndrome would include a prior finding of an isolated elevation
of indirect bilirubin.

9. Patients must have at least one paraffin block available or appropriate number of
unstained slides for analysis of EGFR status.

10. No symptomatic sensory peripheral neuropathy of ≥ grade II at baseline.

11. Non-pregnant and non-lactating

- Women of child bearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG within 72
hours prior to initiation of treatment. This is because DNA alkylating agents are
known to be teratogenic, and the effects of irinotecan, OXAL, 5-FU and C225 on a
developing fetus at the recommended therapeutic doses are unknown.

- Women of child bearing potential includes:

- any female who has experienced menarche and who has not undergone surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral
oophorectomy) or

- is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months] or

- women on hormone replacement therapy [HRT] with documented serum follicle
stimulating hormone (FSH) level > 35 mIU/mL

- women who are using oral, implanted or injectable contraceptive hormones or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy or practicing
abstinence or where partner is sterile (eg, vasectomy), should be considered
to be of child bearing potential.

- Should a woman become pregnant or suspect she is pregnant while participating on
on this study, she should inform her physician immediately. Because the risk of
toxicity of these agents in nursing infants is also unknown, breastfeeding should
be discontinued.

12. No known central nervous system metastases or carcinomatous meningitis.

13. No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung.

14. No pleural effusion or ascites that causes ≥ grade 2 dyspnea.

15. No predisposing colonic or small bowel disorders in which the symptoms are
uncontrolled as indicated by baseline pattern of > 3 watery or soft stools daily in
patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy may
be entered at investigator discretion.

16. No prior exposure or known sensitivity to chimerized or murine antibodies, C225 (or
other EGFR inhibitors) or any tyrosine kinase inhibitors

17. No significant history of cardiac disease, such as unstable angina, CHF, MI, stroke or
a LVEF below the institutional range of normal on a baseline multiple gated
acquisition (MUGA) or echocardiogram.

18. Patients must not have an uncontrolled seizure disorder, or active neurological
disease.

19. Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to
registration.

20. Required Initial Laboratory Values:

- Granulocytes ≥ 1500/ µl

- Hemoglobin ≥ 9.0 gram/dL (patient may be transfused to meet this criterion)

- Platelet count ≥ 100,000/ µl

- Creatinine ≤ 1.5 x Upper limits of normal (ULN)

- Bilirubin ≤ 1.5 mg/dL

- AST ≤ 5.0 x ULN

- Albumin ≥ 2.5 gram/dL