Background: Interleukin 1 alpha (IL-1a) is a pro-inflammatory cytokine that initiates and propagates sterile inflammatory responses. IL-1a is present on the surface of tumors, and released from necrotic cells within the microenvironment, where it upregulates MMPs, VEGF, chemotactic cytokines, and IL-6 contributing to tumor growth and infiltration of the microenvironment by T-regulatory cells and tumor associated macrophages. IL-1a is also found on the surface of platelets and activates vascular endothelium allowing for circulating tumor cells to establish new areas of metastasis. Specific blockade of IL-1a with the true human IgG1k antibody MABp1, is expected to deprive the tumor of its ability to grow, spread, and evade immune surveillance. A phase I/II study showed radiographic evidence of tumor response in mCRC patients, as well as clinically meaningful improvement in cancer associated symptoms, with no significant toxicity. In the context of this therapy, the improvement in key cancer symptoms, including reversal of lean body mass loss, fatigue, and anorexia, is the direct result of an anti-neoplastic effect and is expected to correlate with an overall survival benefit. Methods: This “Phase III Study of MABp1 in Patients With Advanced Colorectal Cancer (XCITE)” is a global study of 600 patients, ECOG-PS 0-2, metastatic CRC refractory to oxaliplatin, irinotecan, fluoropyrimidine, and EGFR-inhibitors if KRAS wildtype. Patients are randomized 2:1 to receive MABp1 7.5 mg/kg iv every two weeks plus best supportive care (BSC) versus placebo (iv Q2 week) plus BSC. BSC does not include any other therapy with proven anti-cancer activity. The primary endpoint is OS, with secondary endpoints of PFS, ORR, change in lean body mass, and QoL. Patients continue on trial until clinical or radiographic progression as defined by the immune related response criteria (irRC). The study is powered to show a clinically meaningful improvement in OS, evaluated by log-rank test with a one-sided alpha of 0.025. As of September 2015, enrollment is currently underway in the United States and Europe, and results of the first interim analysis are expected in 2016. [NCT01767857]. Clinical trial information: NCT01767857