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3017 Background: Mutations of Ras/Raf lead to a sustained and constitutive activation of ERK pathway. MEK1/2 is the only enzyme that activates ERK1/2; consequently MEK1/2 is a potential target to inhibit in cancers with an activated ERK pathway. RO4987655, a potent, highly selective ATP non-competitive MEK1i with an excellent selectivity profile, was tested in a 3+3 Ph1 study design. Objectives were determination of maximum tolerated dose (MTD), recommended Ph2 dose (RP2D), dose limiting toxicities (DLTs), safety/tolerability, PK/ PD and clinical activity. METHODS: Patients (pts) with advanced/metastatic solid tumors received oral RO4987655 administered on a continuous daily dosing (QD) from 1-2.5 mg then twice daily (BID) from 3-21 mg total daily dose in 28 days (D) cycles. Blood PK samples were collected on cycle 1 (C1) [D 1, 8, 15 and 22]. Molecular target suppression was measured by pERKi in PBMC on C1 (D1, D15). Paired skin and tumor biopsies (optional) (baseline, C1D15) and sequential FDG-PET scans (baseline, C1D15, C3D1) were taken. Efficacy was measured as per RECIST. RESULTS: 49 pts in 12 cohorts were enrolled at 4 sites. Mean age 52 y, ECOG 0-1, previous chemotherapy lines median 3 (0-10). Common tumor types included melanoma (27), CRC (11) and NSCLC (3). Four reversible DLTs were observed: CPK elevation (17 mg (n=1), 21 mg (n=2) and blurred vision (21 mg). MTD and RP2D were defined as 17 mg. Most commonly related adverse events included skin (91%), GI (57%), eye (26%) and CPK disorders (44%). PK profiles showed dose-linearity, a half-life of 4 to 6 hrs and drug accumulation ~ 2 fold at steady-state. High (mean 75%) and sustained (90% of time >IC50) pERKi was observed in PBMC at RP2D. FDG PET showed large decrease in SUV at RP2D (-47%, -90% to +29%) (mean, range) which correlated with PBMC pERKi in melanoma pts. PRs and SDs (>=4 mo) were observed in 2 and 5 melanoma, respectively. CONCLUSIONS: RO4987655 showed acceptable and manageable safety profile. PK was linear for the tested dose range with moderate inter-pt variability. PD activity in PBMC associated with large metabolic FDG-PET response and preliminary encouraging antitumor activity were demonstrated at the RP2D.


Journal article


J Clin Oncol

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