MethylGene Inc reported preliminary phase-I data for MGCD265, an oral, multi-targeted kinase inhibitor for cancer that targets the c-Met, VEGF, Ron and Tie-2 receptor tyrosine kinases. Preliminary data from the two clinical trials (Trials 102 and 101) evaluating the compound in solid tumours were published in the proceedings from the American Society of Clinical Oncology's (ASCO) annual meeting. The abstracts with additional updated information describe the favourable safety profile and early signs of activity at doses tested.

The objectives of the two phase-I dose-escalation trials were to evaluate the safety, pharmacodynamics (PD) and pharmacokinetics (PK) of MGCD265 when administered orally to patients with advanced metastatic or unresectable solid tumours that were refractory to standard therapy. The starting dose for both trials was 24mg/m2. In Trial 102, MGCD265 is administered daily every other week over a 28-day cycle, whereas in Trial 101, MGCD265 is administered daily on a continuous basis over a 21-day cycle.

MGCD265 demonstrated early signs of activity at doses tested and a favourable safety profile.

To date, 16 patients have been enrolled in Trial 102 and 14 patients in Trial 101. Patients received doses of MGCD265 ranging from 24 mg/m2 to 255 mg/m2 with the maximum tolerated dose still being investigated. No dose-limiting toxicities have been observed.

In Trial 102, 12 patients have been evaluated for efficacy at dose levels of 24, 48, 96 and 192 mg/m2. Of these patients, five experienced stable disease per RECIST criteria, including one patient with aggressive bladder cancer who remains on MGCD265 treatment after ten cycles and a medullary thyroid cancer patient who experienced tumour shrinkage. Interestingly, an archived tumour biopsy obtained prior to MGCD265 treatment from the patient with aggressive bladder cancer shows c-Met expression and phosphorylation. In Trial 101, ten patients have been evaluated for efficacy at dose levels of 24, 48, 96 and 150 mg/m2. Two of these patients experienced stable disease per RECIST criteria.

Across both studies, MGCD265 appears to have a good safety profile at the doses administered with only four drug-related grade two adverse events and no grade three or higher drug-related adverse events in the 26 patients evaluated for safety. The most frequently reported drug-related grade two adverse event was diarrhoea.

The compound also demonstrated encouraging PD changes in the VEGF, HGF and shed c-Met plasma markers. The preliminary PK findings for MGCD265 also indicated a dose-dependent increase in exposure with a mean half-life of approximately 26 hours.

"We are pleased with the overall safety and pharmacokinetic data compiled to date, as well as the early signs of activity in several of the treated patients," said Donald F Corcoran, president and chief executive officer of MethylGene. "Our goal is to begin our phase-II programme with a phase-I/II combination trial with Tarceva or Taxotere in the third quarter of 2009 as MGCD265's mechanism of action appears to synergize with these anticancer agents."

MethylGene will continue to dose escalate in the two ongoing phase-I trials and commence a phase-II programme with the initiation of a randomized phase-I/II combination trial with MGCD265 and Tarceva or Taxotere focused on non-small cell lung cancer (NSCLC) patients. MethylGene has demonstrated preclinical synergistic in vivo efficacy and tolerability of MGCD265 in combination with both agents. The Tarceva combination is of particular interest, since it has been shown that c-Met and EGFR functionally cooperate. The simultaneous inhibition of c-Met and EGFR has demonstrated enhanced anti-tumour activities in multiple in vivo models. Importantly, c-Met amplification has been described as a mechanism of resistance to EGFR inhibitors in NSCLC patients; therefore, blocking c-Met offers a compelling rationale to overcome resistance to EGFR inhibitors in the clinic.

MethylGene is a publicly-traded, clinical stage, biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for cancer.