Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

PURPOSE: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5FU) chemoradiation (CRT) in patients with locally advanced rectal cancer (LARC). EXPERIMENTAL DESIGN: Stage II/III rectal cancer patients were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the maximum tolerated dose (MTD). Following a 5-day trametinib lead-in, with pre- and post-treatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5FU 225 mg/m(2)/day and 28 daily fractions of 1.8 Gy (total 50.4Gy). The primary endpoint was to identify the MTD and recommended phase 2 dose. Immunohistochemistry (IHC) staining for phosphorylated -ERK (pERK) and genomic profiling was performed on the tumor samples. RESULTS: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well-tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathological complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. CONCLUSIONS: The combination of trametinib with 5FU-CRT is safe and well-tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.