A phase I study of the gamma-secretase inhibitor RO4929097 and capecitabine in refractory solid tumors.

Abstract

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 19 patients are evaluable for toxicity and PK data is available for 11 patients. One DLT has been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2 confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12 cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of RO4929097 all significantly decreased on day 10 compared to day 3, with an increase in clearance for all doses. The half-life was significantly shorter in dose level 3 (p=0.0012) and dose level 4 (p=0.0126) compared to dose level 1. Conclusions: RO4929097 plus cape was well tolerated. Activity was seen in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. However, all plasma concentrations of RO4929097 were above those needed for Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape 1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended phase II dose. [Table: see text]