Daily administration of MGCD265 to patients with solid tumors in a dose-escalation phase I study (study 265-101).

Abstract

3106 Background: MGCD265 is an orally-available tyrosine kinase inhibitor that targets Met, VEGFR-1, -2, -3, Tie-2 and Ron. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered once daily as a continuous 21-day cycle. Cohorts of 3-4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Response is assessed every 2 cycles by RECIST criteria and plasma makers (VEGF, HGF, shed Met and soluble VEGFR2) are being analyzed. Results: The first18 patients received capsules of MGCD265: 4 patients at 24 mg/m2; 3 patients at 48 mg/m2; 4 patients at 96 mg/m2; 3 patients at 150 mg/m2 and 4 patients at 300 mg/m2. Hypertension was observed in one patient at 300 mg/m2 during the first cycle of treatment. This event was considered to be a dose limiting toxicity. Grade 2 adverse events considered at least possibly related to the treatment included: hypertension, anemia, nausea and diarrhea. A tablet formulation was recently introduced at 150 mg/m2 (n=4) and at the 250 mg/m2 dose levels. To date, 5 patients have experienced stable disease. Available archived biopsies obtained prior to MGCD265 treatment from 3 of these 5 patients showed Met protein expression and autophosphorylation. Preliminary PK data indicate a Tmax of approximately 5 hours with a long half-life (∼26 hours). PK profile from tablets and capsules appears similar based on MGCD265 clinical studies. At 150 mg/m2, the steady state plasma concentration is anticipated to be in the range of the exposure at an efficacious dose in xenograft models of Met sensitive tumors. Preliminary PD analyses indicate modulation of VEGF by MGCD265. Conclusions: To date, daily oral administration of MGCD265 has been found to be well tolerated with early signs of activity and at 150 mg/m2, the human exposure is predicted to be in the range of an efficacious dose in preclinical Met sensitive models. In the absence of significant toxicity, this dose could be considered a phase II dose. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MethylGene MethylGene MethylGene MethylGene