Background: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective radiographic tumor regression. Somatostatin analogues and biologics yield prolonged progression-free survival (PFS) but minimal overall response rates (RRs). Historical studies reporting the highest RRs and longest PFS intervals include regimens with cytotoxic chemotherapy, such as streptozocin. Recent retrospective and small, prospective studies, suggest that temozolomide is similarly active but less toxic than streptozocin-based therapy. The proposed study will provide prospective data on response rates and progression-free survival associated with temozolomide or temozolomide in combination with capecitabine, and will also assess the relative efficacy of these two regimens. Methods: E2211 is a two-arm, multi-center, randomized phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine (750 mg/m2 PO BID days 1-14) and temozolomide (200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. Eligibility criteria include: metastatic or unresectable, low or intermediate grade pancreatic NETs, progression within preceeding 12 months, and no prior temozolomide, DTIC, capecitabine, or 5-FU therapy. Primary endpoint is PFS; secondary endpoints are Overall Survival (OS), RR, safety, and MGMT status as evaluated by immunohistochemistry and promoter methylation status. This study will require a minimum of 138 patients (or a maximum of 145 patients to allow for 5% ineligibility) to be accrued at the rate of 6 patients per month. With 23 months of accrual time and 13 months of follow-up (3 years total study time), this trial will have at least 81% power to detect a difference in median PFS between the treatment arms of 9 versus 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the overall 0.20 significance level. First patient entered onto the study in August 2013. As of January 2015 a total of 67 (46% of target) patients have been recruited. Clinical trial information: NCT01824875. Clinical trial information: NCT01824875