A phase I study of oral administration of MGCD265 in patients with advanced malignancies (study 265-102).

Abstract

3108 Background: MGCD265 targets the Met, VEGFR-1, 2, 3, Ron and Tie-2 tyrosine kinases, which play key roles in tumor development. Methods: This is an open-label, dose escalation study of oral MGCD265 administered once daily on a 1 week on/1 week off schedule of each 28-day cycle. The starting dose was 24 mg/m2 with doubling of dose between cohorts if no grade 2 drug-related toxicity or dose-limiting toxicities (DLT) are observed. Results: The first 20 patients recruited received the capsule formulation of MGCD265 (4 patients at 24 mg/m2, 4 patients at 48 mg/m2, 3 patients at 96 mg/m2, 3 patients at 192 mg/m2, 3 patients at 255 mg/m2, and 3 patients at 340 mg/m2). A tablet formulation was recently introduced and 8 additional patients have been recruited using this formulation: 4 patients at 192 mg/m2and 4 patients at 255 mg/m2. No DLTs have been observed to date but grade 2 adverse events considered at least possibly related to the treatment included diarrhea, nausea, neutropenia, and intermittent dizziness. To date, 7 patients have experienced stable disease per RECIST. One patient (at 96 mg/m2) with sarcomatoid bladder cancer was stable for 10 cycles with significant pharmacodynamic changes in Met and phospho-Met proteins, as well as a decrease in intact vascular structures, in a post-treatment biopsy sample. The preliminary pharmacokinetic (PK) analysis demonstrates a linear exposure up to 192 mg/m2. At this dose, the PK profile from tablets and capsules appears similar. The PK determination above 192 mg/m2 is in progress. At 192 mg/m2, the steady state plasma concentration is in the range of the exposure at an efficacious dose in xenograft models of Met sensitive tumors. Conclusions: To date, intermittent administration of MGCD265 was found to be well tolerated. Early signs of clinical activity and PD changes have been demonstrated and at 192 mg/m2, the human exposure is 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