Background: Despite recent advances in cytotoxic chemotherapies and targeted agents, metastatic colorectal cancer (mCRC) continues to be an area of great unmet medical need. Patients with mCRC are typically treated with a fluoropyrimidine plus oxaliplatin or irinotecan, with or without an anti-angiogenic agent or monoclonal antibody to epidermal growth factor receptor. Although these regimens are considered standard of care, they are only moderately effective, and more-active regimens are needed. Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway is associated with resistance to chemotherapies with different mechanisms of action, including taxanes and DNA-damaging agents, in nonclinical models. In the clinic, PI3K pathway activation in tumors has been correlated with decreased response to therapy and worse clinical outcomes. The combination of PF-05212384 (intravenous PI3K/mammalian target of rapamycin inhibitor) and irinotecan was additive in preclinical mCRC models and showed preliminary antitumor activity with acceptable tolerability in a phase I study (B1271002; NCT01347866) in patients with cancer, including mCRC, warranting further exploration of irinotecan-based combination regimens. Methods: This global study includes a dose escalation, phase Ib portion to evaluate dose limiting toxicities (primary endpoint) and determine the recommended phase II dose of PF-05212384 combined with FOLFIRI. A separate lead-in cohort to confirm the safety of the PF-05212384/FOLFIRI combination will be conducted at clinical sites in Japan. Then, a randomized phase II portion will investigate whether PF-05212384 plus FOLFIRI is superior to bevacizumab plus FOLFIRI in prolonging progression-free survival (primary endpoint) in patients with mutated or wild-type KRAS mCRC and disease progression on a first-line oxaliplatin-containing regimen or with progression within six months of an oxaliplatin-containing regimen in the adjuvant setting. Secondary endpoints include safety, overall survival, and biomarker correlations associated with the PI3K pathway. This trial is now recruiting. Clinical trial information: NCT01937715.