A Phase Ib/II, multicenter, open label, study of LEE011 in combination with MEK162 in adult patients with NRAS mutant melanoma
Study of safety and efficacy in adult melanoma patients with NRAS mutant Tumors.
Purpose and rationale:
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cyclinD3 complexes, with concentration resulting in 50% inhibition (IC50) values of 10 nM and 39 nM, respectively, in isolated enzyme assays. It is inactive against the majority of other kinases. MEK162 is an oral, ATP non-competitive, highly selective inhibitor of MEK 1/2. The compound has nanomolar activity against purified MEK enzyme (IC50=12 nM) and inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell lines with IC50 values as low as 5 nM.
Based on pathway biology and preclinical data, the combination of LEE011 and MEK162 has the potential to be effective in patients with NRAS mutant melanoma. In the phase Ib, the primary purpose is to establish the MTD(s)/RP2D of the LEE011 and MEK162 combination. Once the MTD(s)/RP2D have been determined, the phase II part will begin in order to assess antitumor activity of LEE011 and MEK162 combination.