Inclusion Criteria:

Patients are eligible to be included in the study only if they meet all of the following criteria:

1. Histologic diagnosis of colorectal cancer.
2. Performance status of 0, 1, or 2 on the ECOG performance status schedule.
3. Have had documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST; Therasse et al. 2000) within 3 months after receiving FOLFOX plus bevacizumab as first-line therapy for locally advanced or metastatic disease, or within 6 months after receiving FOLFOX with or without bevacizumab in the adjuvant setting.
4. Standard radiation therapy for rectal cancer is allowed. Patients must have recovered from the toxic effects (except for alopecia) of the treatment prior to study enrollment. Prior radiotherapy must be completed 4 weeks before study entry. Lesions that have been radiated in the advanced setting cannot be included as sites of measurable disease unless clear tumor progression has been documented in these lesions since the end of radiation therapy.
5. At least one uni-dimensionally measurable lesion meeting RECIST guidelines (at least 10 mm in longest diameter by spiral computerized tomography [CT] scan, or at least 20 mm by standard techniques). Positron emission tomography [PET] scans and ultrasounds may not be used.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Have received treatment within the last 4 weeks with a drug that has not received regulatory approval for any indication at the time of study entry.
2. Have previously completed or withdrawn from this study or any other study investigating enzastaurin, irinotecan, or cetuximab.
3. Have a serious concomitant systemic disorder (eg, active infection including HIV, or cardiac disease) that, in the opinion of the investigator, would compromise the patient's ability to adhere to the protocol.
4. Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV.
5. Have a prior malignancy (other than colorectal cancer, or adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer), unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years previously.