Abstract B51: A phase I dose-escalation study of MGCD265 in patients with advanced malignancies (study 265-102)

Abstract

Abstract Introduction: MethylGene has developed a small molecule inhibitor, MGCD265, that inhibits c-Met, Ron, all three members of VEGFR family and Tie-2, thereby inhibiting multiple pathways involved in tumor growth, metastasis and angiogenesis. The primary objectives of this study are to determine the maximum tolerated dose and the safety profile of MGCD265 administered with interruption to patients with advanced malignancies. Methods: This is a multicenter, 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. 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 was 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 continued until disease progression or toxicity. Response, as a secondary objective, was assessed every 2 cycles by RECIST criteria. Results: Twenty patients (20) have been recruited to date: 4 patients in cohort 24 mg/m2; 4 patients in cohort 48 mg/m2; 3 patients in cohort 96 mg/m2; 3 patients in cohort 192 mg/m2; 3 patients in cohort 255 mg/m2; and 3 patients in cohort 340 mg/m2. The overall age range is 40 to 72 years and the gender distribution among the cohorts is 13 female to 7 male patients. No DLTs have been observed to date but grade 2 adverse events (AE) considered at least possibly related to the treatment included diarrhea (n=2), nausea (n=1) and intermittent dizziness (n=1). No grade 3 or higher drug-related AE have been reported. To date, 5 patients have experienced stable disease per RECIST. One patient with a sarcomatoid bladder cancer (dosed at 96 mg/m2), who was progressing prior to study entry, has been treated for 12 cycles. An archived biopsy obtained prior to MGCD265 treatment from this patient shows c-Met expression and autophosphorylation. One patient with medullary thyroid cancer experienced tumor shrinkage (−10%). Conclusions: To date, intermittent administration of MGCD265 was found to be well tolerated with preliminary signs of activity. Recruitment of additional cohorts is underway. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B51.