A phase Ib study of investigational pan-RAF kinase inhibitor MLN2480 plus investigational TORC1/2 inhibitor MLN0128, investigational Aurora A kinase inhibitor alisertib (MLN8237), or paclitaxel in patients (pts) with advanced solid tumors.

TPS2609 Background: Signaling hyperactivation secondary to MAPK pathway aberrations are common. RAF kinases play key roles in the RAS/RAF/MEK/ERK signaling cascade, representing potentially valid therapeutic targets. In a phase 1 study, single-agent MLN2480 had an acceptable safety profile, expected pharmacodynamic effects and preliminary antitumor activity (Middleton et al, ENA 2014, Abstract 364). Preclinically, MLN2480 has shown synergistic/additive effects in xenograft models and cell lines when combined with MLN0128, alisertib or the taxane, docetaxel. Potential overlapping toxicities of each combination are expected to be manageable, with no apparent risks for clinically meaningful pharmacokinetic (PK) drug–drug interactions based on in vitro ADME data and exposures achieved clinically. Methods: This three-arm, open-label study (NCT02327169) is the first-in-human study for MLN2480 + MLN0128/alisertib/paclitaxel. Primary objective is to evaluate the safety, tolerability, and MTD of each combination. ...