Background: Activation of the EGFR results in cell proliferation and survival via the RAS/RAF/MAPK, and PI3K/PTEN/AKT signalling pathways. Mutations in the KRAS gene result in a constitutively active protein that is independent of the EGFR and therefore is not inhibited by anti-EGFR monoclonal antibodies. However, recent retrospective studies have shown that aberrations in other down stream signalling molecules also confer resistance to EGFR antagonists, including mutations in BRAF and PI3K, and loss of the PTEN tumour suppressor molecule. The mammalian target of rapamycin (mTOR) is a key downstream regulatory protein that is activated via the PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to blockade of the EGFR may cause a more profound anti-tumour effect by overcoming upstream mechanisms of resistance. In EGFR-resistant colon cancer cell lines, in vitro and in vivo studies of the combination of everolimus and an EGFR inhibitor resulted in reduced tumour growth and resensitised resistant cancer cells to EGFR inhibition (Bianco. B J Cancer 2008:923-930). Methods: This is a phase Ib/II, open label, non-randomised study. Eligibility criteria include age ≥ 18 years, metastatic colorectal cancer that is KRAS wild type, following failure of first-line oxaliplatin and fluoropyrimidine combination chemotherapy, with adequate bone marrow reserve and organ function. Patients receive IV irinotecan and panitumumab every 2 weeks, with everolimus administered orally thoughout the 14 day cycle. The starting dose is irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose finding will use a standard 3+3 design with the MTD being defined as the dose with DLTs in 1/6 or fewer patients. Following determination of the MTD, the phase II component of the study will begin for which the primary endpoint is response rate. A total of 50 patients will be recruited. Correlation of response rate with BRAF mutation, expression of PTEN, ERK, AKT, mTOR, and pS6K will be performed.