A Phase I Study Of The Gamma-Secretase Inhibitor Ro4929097 And Capecitabine In Refractory Solid Tumors.

3101 Background: RO4929097 is a oral inhibitor of gamma-secretase, which results in Notch signaling inhibition. Prior work has demonstrated that Notch-signaling inhibition enhances chemosensitivity of colon cancer cells. This study sought to combine RO4929097 with capecitabine (cape) and determine maximum tolerated dose (MTD), toxicities and efficacy. Preclinical and prior phase I work demonstrated possible autoinduction of RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and cape was planned. Methods: Adult patients with refractory solid tumors were eligible and received RO4929097 and cape at a fixed dose of 1000 mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle according to a 3+3 design. Cape was administered for 14 days and the RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels have been completed (20, 30, 45 and 68 mg); 18 of ...