e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered 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. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]
Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial