471P - A phase I, dose-escalation study of MGCD265, a multi-targeted oral tyrosine kinase receptor inhibitor, for treatment of advanced solid tumors

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Drug Development
Presenter Herbert Hurwitz
Authors H. Hurwitz1, C.K. Kollmannsberger2, M. Juretic3, J. Wang3, M. Fournel3, C. Bonfils3, C. Maroun3, R.W. Humphrey3, J. Besterman3, G. Shapiro4
  • 1Duke University Medical Center, 27710 - Durham/US
  • 2Bcca Vancouver Cancer Centre, University of British ColumbiaDivision of Medical Oncology, CA-V5Z 4E6 - Vancouver/CA
  • 3Clinical Affairs, Methylgene, Inc, Montreal/CA
  • 4Oncology, Dana-Farber Cancer Institute, Boston/US



MGCD265 is a multikinase inhibitor with activity against Met, VEGFR 1, 2 and 3, Tie-2 and Ron that has been shown in preclinical models to possess broad antitumor effects.


Patients with advanced malignancies were enrolled in a phase I, open-label, dose-escalation study. Oral MGCD265 was administered daily over a 3-wk cycle, at a starting dose of 24 mg/m2 once daily. QD and BID dosing were tested sequentially. The study's primary aim was to determine the safety profile of MGCD265, including maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Pharmacokinetics, pharmacodynamics and antitumor activity were also evaluated.


To date, 61 patients have been enrolled, with dose escalation up to 313 mg/m2 BID. Increasing dose frequency to BID increased exposure of MGCD265 by approximately twofold. Drug exposure achieved to date is in the range where tumor growth inhibition was observed with Met-sensitive preclinical models. Dose-dependent inhibition of Met phosphorylation was demonstrated in an ex vivo model using patient plasma, with up to 55% inhibition observed at doses to date. MTD has not yet been reached, and dose escalation continues. MGCD265 was well tolerated. DLTs were observed in 5 patients (N = 1 each): fatigue, diarrhea, lipase elevation, pituitary hemorrhage (all grade 3) and hypertension (grade 2, protocol-defined), all occurring in cycle 1 at daily doses ≥ 250 mg/m2. Drug-related grade 3 adverse events beyond cycle 1 were diarrhea, fatigue, elevated lipase and elevated alkaline phosphatase (N = 1 each). Of 51 response-evaluable patients to date, 22 achieved stable disease (SD) for ≥2 cycles, and 7 achieved SD for ≥6 cycles (1 patient up to 12 cycles).


This study supports the safety of MGCD265 in patients with advanced malignancies. There are encouraging early signs of efficacy, with prolonged stable disease noted in several heavily pretreated patients.


H.I. Hurwitz: Research funding from Methylgene, Inc.

C.K. Kollmannsberger: Research funding from Methylgene, Inc.

M. Juretic: Employee of Methylgene, Inc.

J. Wang: Employee of Methylgene, Inc.

M. Fournel: Employee of Methylgene, Inc.

C. Bonfils: Employee of Methylgene, Inc.

C. Maroun: Employee of Methylgene, Inc.

R.W. Humphrey: Employee of Methylgene, Inc.

J. Besterman: Employee of Methylgene, Inc.

G. Shapiro: Research funding from Methylgene, Inc.