Background: This is a CRC cohort analysis from the novel Novartis “Signature” program of tissue-agnostic, genetic alteration specific signal-finding protocols. Potential patients are identified via standard-of-care profiling; we bring the ‘Protocol to the Patient’, with rapid start-up process. Buparlisib (BKM120) is an oral pan-PI3K inhibitor evaluated in this program. Methods: Patients had progressive/relapsed CRC harboring PI3K pathway activated tumors, measurable disease, ECOG PS ≤1, and adequate organ function. A local CLIA-certified test is sufficient for eligibility. Central post hoc broad tumor molecular profiling of genetic alteration is performed. BKM120 was given orally (100 mg) qd. The primary objective is to assess clinical benefit (SD or better at 16 weeks). Statistical design adaptively clusters patients into cohorts for independent analysis for early futility or efficacy. Results: 18 CRC patients were dosed: 10 females, 15 Caucasian, median age 58 years (40-80), all had ECOG PS ≤1. Median prior therapies: 4 (1-13). Actionable alterations present at baseline (local): 10 (55.6%) PIK3CA mutation, 4 (22.2%) PTEN loss (IHC), 3 (16.7%) each PTEN mutated and PIK3R1 mutated. Median time on study was 5.1 weeks (1-16). Frequently observed AEs: nausea (67%), fatigue (39%), vomiting (33%), diarrhea (33%), anxiety (28%) and decreased appetite (28%). Three patients discontinued due to AEs. At week 16: 13 patients did not meet clinical benefit criteria and 5 patients were non-evaluable. Two patients had SD at week 8. Central genomic profiling: DNA from 14 patients was assessed covering a panel of 288 cancer genes. All patients had a mutation in APC, 10 (71%) also had KRAS mutations and 11 (79%) had mutations in TP53. Three patients with the lowest PFS exhibited mutations in ERBB2 and ERBB4. Concordance between local and central lab results was 73%. Conclusions: This program facilitated the enrollment of molecularly profiled CRC patients with PI3K pathway alterations. In this cohort, BKM120 had a manageable safety profile with negligible activity as single agent. Further evaluation can determine the effect of BKM120 in combination with other agents. NCT01833169Clinical trial information: NCT01833169