First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors.

Abstract

2504 Background: AS703026 is a highly selective and potent noncompetitive inhibitor of MEK1/2. AS703026 exhibited strong antiproliferative activity in tumor cell lines with activated mitogen-activated protein kinase (MAPK) signalling, and antitumor efficacy in numerous human tumor xenograft models. This phase I trial was initiated to determine the maximum tolerated dose (MTD) of two AS703026 R. Methods: Pts with solid tumors received oral, fixed doses of AS703026 once a day, on days 1–5, 8–12, and 15–19 (R1) or days 1–15 (R2), of 21-day cycles. Accelerated then modified Fibonacci dose-escalation processes were applied for each R. PK samples and pre- and post-dose peripheral blood mononuclear cells (PBMC) for the measurement of phosphorylated extracellular signal-regulated kinase (pERK) were collected for all pts. Results: As of November 1, 2009, 68 pts (36 pts R1, 32 pts R2) received AS703026 across 10 dose levels [range 1–94 mg/day]. Pt characteristics were median age [range] 60 yrs [34–75] R1, 62 yrs [43–77] R2; males 56% R1, 55% R2; ECOG PS (0/1) 56%/44% R1, 55%/46% R2. Most frequent tumors were colorectal (42% R1, 36% R2) and melanoma (14% R1, 12% R2). Pts received a median of 2 cycles [range] in both R [1–6, R1, 1–11, R2]. Most common adverse events (all grades): asthenia (49% R1, 50% R2), diarrhea (40% R1, 28% R2), acne-like skin reactions (37% R1, 41% R2), nausea (34% R1, 25% R2), constipation (26% R1, 16% R2), vomiting (23% R1, 25% R2). At 28 mg/day, 1/6 pts experienced a DLT (grade 3 liver function test elevation). Visual disturbances were reported at 94 mg/day (66% R1, 33% R2). Plasma concentrations and exposures increased proportionally with dose, with a median tmax of 1.5 hours [range 0.5–4.0] after intake. Complete pERK inhibition was observed in PBMC 2 hours post-intake at doses ≥28 mg/day. Two confirmed partial responses (at 68 and 94 mg/day) were reported in previously-treated melanoma pts. Conclusions: AS703026 showed a good safety and PK profile with complete target inhibition in PBMCs at doses ≥28 mg/day. MTD has not been reached; dose escalation is ongoing. Interestingly, antitumor activity has been observed prior to reaching the MTD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono Amgen Bayer, Merck Serono, Pfizer EMD Serono, Merck Serono