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.

DNA cleavage characteristics of non-protein enediyne antibiotic N1999A2.

N1999A2 (NA2) is a new non-protein antitumor antibiotic that contains a stable 9-membered ring enediyne chromophore similar to a neocarzinostatin chromophore (NCS-chr). We have compared DNA cleavage reactions between NA2 and NCS-chr, and also clarified some characteristics of DNA strand scission by NA2. It was found that: (1) NA2 is considerably stable in nature, (2) the compound intercalates into base pairs of a DNA minor groove and decreases its base-attacking frequency in the order of T>A>> C>G, (3) the base-sequence specificity 5(')-GGT/3(')-CCA presented by NA2 is significantly related to recognition of the base pair with the naphthoate moiety, and (4) the different cleavage property between NCS-chr and NA2 is associated with the presence or absence of an aminoglycoside residue. Based on the results of the site-specific cleavage by NA2 for certain bulged DNAs and a fluorescence study of NA2-DNA oligomer complexes, the DNA interaction mode of NA2 has also been examined. These results provide important information to design a new enediyne molecule for a DNA target.