Phase I and pharmacokinetics/pharmacodynamics study of the MEK inhibitor RO4987655 in Japanese patients with advanced solid tumors.

RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors. METHODS: Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8-93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage. CONCLUSIONS: RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

Transforming mutations of RAC guanosine triphosphatases in human cancers.

Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.