Clinical Effects of MGCD265, an oral Tyrosine Kinase Inhibitor, in Combination with Erlotinib or Docetaxel for Treatment of Advanced Gastroesophageal and Nsclc Tumors

ABSTRACT Background MGCD265, a multikinase inhibitor with nM IC50 against Met, VEGFR 1, 2 and 3, Tie-2 and Ron, has been shown in preclinical models to possess broad antitumor effects. A phase I study was undertaken to assess therapy with MGCD265 and docetaxel or erlotinib for treatment of solid tumors. Methods Patients (pts) with advanced solid tumors were enrolled in an open-label, dose-escalation study using the standard 3 + 3 design. All pts received 3-wk cycles of MGCD265 (p.o. QD or BID) with docetaxel or erlotinib per standard of care, as defined by investigators. Endpoints were safety, pharmacodynamics, pharmacokinetics and antitumor activity of the combination therapy. Results Of 89 pts enrolled, there were 12 cases of NSCLC (docetaxel group) and 9 cases of gastroesophageal (GE) cancer (erlotinib group). Of 10 response-evaluable NSCLC pts, all met criteria for stable disease (SD) for ≥2 cycles (including 2 pts with partial response). Five pts achieved SD for 5-16 mos, with four exceeding time on prior therapy. Two pts have not reached first evaluation. Treatment continues in 3 pts. Four of nine GE pts achieved SD. Three remained stable for 10-18 mos, exceeding time on prior therapy. Treatment continues in 1 pt. A plasma-based assay of Met phosphorylation showed up to 30% inhibition at doses to date. PK analysis is pending. Dose escalation continues. Toxicities were mostly mild to moderate. Nonhematologic adverse event (AEs) ≥ grade 3 were reported in 20% of pts in each treatment arm, and were primarily GI-related. Expected docetaxel–associated hematologic AEs were also observed. Conclusions Preliminary findings from a phase I study suggest that MGCD265 and docetaxel or erlotinib may hold promise for treatment of NSCLC and GE tumors. Clinical response was seen in the majority of NSCLC pts, with almost 50% achieving SD for ≥5 mos. Select GE pts achieved SD for more than 10 mos. AE rates with combination therapy were in the expected range. Disclosure A. Patnaik: Research funding from Methylgene, Inc. K. Papadopoulos: Research funding from Methylgene, Inc. A.W. Tolcher: Research funding from Methylgene, Inc. M. Beeram: Research funding from Methylgene, Inc. M. Tawashi: Employee of Methylgene, Inc. M. Fournel: Employee of Methylgene, Inc. C. Maroun: Employee of Methylgene, Inc. R.W. Humphrey: Employee of Methylgene, Inc. J. Besterman: Employee of Methylgene, Inc. P.J. Ou0027Dwyer: Research funding from Methylgene, Inc.