Background: Epigenetic silencing of O⁶-methylguanine-DNA methyltransferase (MGMT) during colorectal tumorigenesis is responsible for diminished DNA-repair of O⁶-alkylguanine adducts, leading to an enhancing chemosensitivity to alkylating agents such as temozolomide (TMZ). In two phase II studies, we showed that TMZ is effective in heavily pre-treated pts with advanced CRC and MGMT promoter methylation. Other studies in carcinoids cell lines demonstrated synergistic cell kill if 5-fluoracile and TMZ were delivered in a schedule-dependent manner. The CAPTEM regimen consists of TMZ for 5 days at 75 mg/m2/day bid on days 10–14 and capecitabine 750 mg/m2/day bid on days 1–14 of a 28-day cycle. Given the potential synergy of capecitabine and TMZ in MGMT methylated CRC, we planned a randomized study to evaluate the efficacy of CAPTEM versus FOLFIRI after failure of prior first-line oxaliplatin-based treatment in patients with advanced, MGMT methylated, RAS mutated CRC. Methods: This is an open-label, multicenter, randomized phase II trial. Up to 82 pts will be enrolled and randomized in a 1:1 ratio to receive FOLFIRI or CAPTEM as second-line treatment for up to 6 months or up to disease progression or unacceptable toxicity. Efficacy assessments will be performed every 8 weeks. Primary objective is progression-free survival (PFS). According to the results of the GERCOR study, the median PFS during second-line treatment with crossover from FOLFOX to FOLFIRI was 2.3 months. A one-sided log rank test with an overall sample size of 82 subjects achieves 90% power at a 5% significance level to detect an increase in median PFS from 2 months of the control group to 4 months. Secondary objectives: safety, quality of life, response rate and overall survival. Exploratory objectives: identification of potential biomarkers associated with activity of TMZ in tumor tissue (MGMT immunohistochemistry, methylBEAMing and next-generation sequencing) and in plasma (methylBEAMing and miRNA). Clinical trial information: NCT02414009