MErCuRIC results were presented in a poster at the NCRI Cancer Conference in Liverpool, UK on 08 Nov 2016 (Session B, 08:15-11:00). The conference ‘showcases the latest basic, translational and clinical cancer research. It brings researchers together to share ideas and develop collaborations.’
‘MErCuRIC1: A Phase Ia study of MEK1/2 inhibitor PD-0325901 with cMET inhibitor crizotinib in patients with advanced solid tumours’
RAS activating mutations occur in ~55% of metastatic (m)CRC. RASMT and >50% of RASWT mCRC patients do not benefit from anti-EGFR antibodies. c-MET is overexpressed in ~50-60%, amplified in ~2-3% and mutated in ~1-3% of mCRC. Preclinical data support the clinical evaluation of MEK1/2 and METi, particularly in RASMT tumours and RASWT with aberrant c-MET expression. The study’s primary aim was to establish the maximum tolerated dose (MTD) and assess safety/toxicity profile of PD-0325901 MEKi/crizotinib METi in patients with advanced solid tumours using NCI CTCAE V4.03.
Method: A single arm, open-label phase I trial of PD-0325901 with crizotinib in patients with advanced solid tumours, measurable disease, ECOG PS 0-1 and adequate end organ function. Patients received oral PD-0325901 (days 1-21 every 28 days) at doses of 2-8mg BD with oral crizotinib continuously at 250mg OD or 200mg BD, using a rolling-6 design.Crizotinib started after a week lead-in with PD-0325901. Blood samples forpharmacokinetics, pERK and soluble c-MET levels and skin biopsies for pERK levels were collected.
Results: Between 12/2014 and 11/2015 we enrolled 25 patients; Male(13), Female(12), who received 52 cycles in total. Median age 63yrs (range 36-78). MTD was defined at the highest dose; crizotinib: 200mg BD continuously; PD-0325901: 8mg BD days 1-21 every 28 days at which 1/6 patients exhibited dose-limiting toxicity (fatigue). Drug-related adverse events were in keeping with single agent toxicity profiles, including rash, diarrhoea, fatigue, nausea, hypoalbuminemia and visual disturbances. Best clinical response was stable disease at end of cycle 2 in 4/25 patients.
Conclusion: MEK/METi can be given together at pharmacologically active doses. MTD for the PD-0325901/crizotinib combination was 8mg BD (days1-21) and 200mg BD continuously in a 28 day cycle. The combination is now being explored further with an alternate MEKi before expansion into RASMT and RASWT CRC with aberrant c-MET expression.EudraCT: 2014-000463-40.
MErCuRIC Patient Representative with poster at NCRI