Abstract A95: The determination of the maximum tolerated dose (MTD) of MGCD265 on an intermittent schedule: Phase I study results (Study 265-102).

Background: MGCD265 is an orally administered multi-targeted receptor tyrosine kinase (RTK) inhibitor that specifically targets Met RTK and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3). Additional RTK targets include Tie-2 and Ron. These kinases are known to be involved in tumor development and angiogenesis. Methods: This was a Phase I dose-escalation study in patients with advanced solid tumors (classic 3+3 design). Oral MGCD265 was administered intermittently (one week on/one week off) over 28-day cycles. The primary objectives were to determine the MTD, dose limiting toxicities (DLTs) and safety of MGCD265. Secondary objectives were pharmacokinetics (PK) profile, pharmacodynamic (PD) change, and anti-tumor activity of MGCD265. Results: Forty seven patients with advanced solid tumors were recruited (median age: 60 years old, M/F: 23/24, ECOG 0/1/2: 10/33/4). MGCD265 was administered once a day (QD) in the initial cohorts and then twice daily (BID) in the last two cohorts. The observed DLTs were grade 3 mood alteration and grade 3 fatigue in one patient and grade 3 hemoptysis in another patient at the dose of 170 mg/m 2 BID (n=6). Therefore, the previously tested dose level of 128 mg/m 2 BID was determined to be the MTD. The most frequent treatment-related adverse events included diarrhea, nausea, and fatigue. Most of these AEs were reported as grade 1 or 2 in severity. Fourteen patients experienced serious AEs; none were considered related to study medication. MGCD265 has a terminal half-life of approximately 23 hours. Exposure on the QD schedule appeared to increase with increasing doses from 24 mg/m 2 up to 96 mg/m 2 and approached a plateau with subsequent dose increases up to 340 mg/m 2 . With the BID schedule, higher exposures at steady state were achieved and a plateau was less evident with the two doses tested (128 and 170 mg/m 2 BID). Four patients (papillary renal cell, sarcomatoid bladder, neuroendocrine, and head & neck cancers) had prolonged stable disease (range: ∼6–14 cycles). The patient with sarcomatoid bladder cancer was stable for 10 cycles and exhibited decreases in Met and phospho-Met protein expression, as well as a change in intact vascular structures, in a post-treatment biopsy sample. Conclusions: MGCD265 is safe and well tolerated when using the intermittent schedule of administration. Based on the results obtained in other trials with daily administration, MGCD265 will be administered continuously in future studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A95.