The purpose of this study is to determine whether an optimal dose of [6R] 5,10-methylenetetrahydrofolate (arfolitixorin) in combination with pemetrexed are effective in pre-operative treatment of patients with resectable rectal cancer.

Inclusion Criteria:

• Pathological/ cytological diagnosis of adenocarcinoma of the rectum. Patients must have operable rectal cancer that is amenable to surgery.
• No prior therapy for rectal cancer
• Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1
• Adequate organ function
• Patient compliance and geographic proximity that allow adequate follow-up
• For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen during and for 3 months after treatment; must have a negative serum or urine pregnancy test and must not be lactating.
• For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 3 months after treatment.
• Estimated life expectancy of at least 12 weeks
• Signed informed consent
• At least 18 years of age

Exclusion Criteria:

• Concurrent administration of any other anti-tumor therapy.
• Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
• Serious concomitant systemic disorders (e.g., active infection including HIV, cardiac disease) that in the opinion of the investigator would compromise the patient's ability to complete the study.
• Have previously completed or withdrawn from this study or any other study investigating pemetrexed.
• Are pregnant or breast-feeding.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• History of significant neurological or mental disorder, including seizures or dementia.
• Inability to interrupt aspirin or other nonsteroidal anto-inflammatory drugs (NSAIDs)
• Presence of clinically relevant third-space fluid collection that cannot be controlled by drainage or other procedures prior to study entry.
• Inability or unwillingness to be given 5,10-methylenetetrahydrofolate, vitamin B12 or dexamethasone.