Rectal Cancer Consortium

Specific gene mutations have become targets for specific therapies. For example lung
adenocarcinomas with an EGFR (epidermal growth factor receptor) mutation can be targeted
with an EGFR tyrosine kinase inhibitor achieve striking and durable responses and improved
survival. Another example is the identification of the echinoderm microtubule-associated
protein-like 4/anaplastic lymphoma kinase (ALK) gene fusions which have led to significant
therapeutic gains in the small percentage of patients with lung adenocarcinoma whose cancers
exhibit this mutation. Specific mutations have been found in colon cancer and specific drugs
targeting these gene alterations are in development. As future therapeutic protocols
specific for these mutations are developed, patients who agree may be notified of their
eligibility for these studies.

The aims of this study are to link mutational analyses with clinical outcome. It is
recommended that patients receive 8 cycles of mFOLFOX6 (modified FOLFOX) and 50.4 Gy
radiation with concurrent fluoropyrimidine.

Inclusion Criteria:

- Patients must have histologically proven adenocarcinoma of the rectum with no
evidence of distant metastases.

- The tumor must be clinically Stage II (T3-4 N0) or III (T1-4 N1-2).

- Patients must have no evidence of distant metastases including liver metastases,
peritoneal seeding, or inguinal lymphadenopathy.

- Patients who completed or are actively enrolled in the CONTRE study and patients
undergoing treatment for rectal cancer following the TNT (Total Neoadjuvant
Treatment) format (see below) for whom sufficient tissue is available for the
required research analyses may be enrolled in this study retroactively.

- For those who have not yet received treatment for rectal adenocarcinoma, these
patients must not have received prior chemotherapy or pelvic radiation for rectal
cancer, or prior pelvic radiation for any other malignancy that would prevent the
patient from receiving the required radiation treatments for this study.

- Patients must not have an active concurrent invasive malignancy other than
non-melanoma skin cancers. Patients with malignancies diagnosed within 5 years prior
to randomization which have been effectively treated and are deemed to be at low risk
for recurrence are eligible.

- Patients must be > 18 years of age, ECOG (performance status) 0-1.

- ANC (absolute neutrophil count) >1,500/µl, platelets >100,000/µl, total bilirubin
<2.0 mg/dl or direct bilirubin <1.0 mg/dl, alkaline phosphatase <3xULN, ALT <3xULN,
creatinine <1.5xULN.

- Signed informed consent; able to comply with study and/or follow- up procedures

- Peripheral neuropathy < grade 1.

- The intention of the treating physicians is to administer Total Neoadjuvant Treatment
as per the suggested treatment guidelines in section 4 and section 5 or as per
standard institutional policies.

Exclusion Criteria:

- Evidence of metastatic disease.

- Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid,
squamous cell carcinoma, cloacogenic carcinoma, etc.

- Pregnancy or lactation at the time of proposed randomization. Eligible patients of
reproductive potential (both sexes) must agree to use adequate contraception.

- Synchronous invasive colon cancer.

- Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
preclude the patient from receiving any chemotherapy treatment option or would
prevent required follow-up.

- Patients with active inflammatory bowel disease, abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 6 months prior to Day 0 or other
serious medical illness which might limit the ability of the patient to receive
protocol therapy.

- Known hypersensitivity to 5-fluorouracil or oxaliplatin

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

- Insufficient tumor tissue available for the required genomic analyses and patient
unable or unwilling to undergo repeat examination and biopsies.