456P - Multicenter, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors: prelimi...

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Clinical research
Basic Scientific Principles
Presenter Alex Adjei
Authors A.A. Adjei1, P. Lorusso2, A. Ribas3, J.A. Sosman4, G.K. Dy5, B. Chmielowski6, P. Lipman7, X. Zhou8, E. Gangolli9, V. Bozón10
  • 1/
  • 2Oncology, Karmanos Cancer Institute, Detroit/US
  • 3Oncology, UCLA Jonsson Comprehensive Cancer Center, Los Angeles/US
  • 4Hematology/oncology, Vanderbilt University Medical Center, Nashville/US
  • 5Medicine Oncology, Roswell Park Cancer Institute, 14263 - Buffalo/US
  • 6Medicine, University of California Los Angeles, Los Angeles/US
  • 7Biostatistics, Millennium Pharmaceuticals, Inc., Cambridge/US
  • 8Clinical Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge/US
  • 9Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge/US
  • 10Oncology, Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge/US



TAK-733 is an investigational, orally available, selective, non-ATP-competitive, allosteric inhibitor of MEK1/2 shown to have anti-tumor activity in multiple xenograft models. In this first-in-human ph 1 study (NCT00948467), we evaluated safety, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and efficacy of TAK-733 in pts with advanced solid tumors.


Pts aged ≥18 y, with ECOG PS 0–2 and radiographically or clinically evaluable tumors were eligible. Pts received TAK-733 QD on d 1–21 in 28-d cycles; doses escalated in a modified 3 + 3 design based on dose-limiting toxicities (DLTs) in cycle 1 to determine MTD. Plasma and blood samples for PK and PD analysis were collected pre-dose on d 1, 8, 15 and 21 and post-dose d 1 and 21 in cycle 1.


As of March 16, 2012, 44 pts median age 58 (range 24 − 75) and 50% male, received TAK-733 (dose mg, [n]: 0.2, [1]; 0.4, [1]; 0.8, [2]; 1.6, [2]; 3.2, [4]; 4.4, [4]; 6, [4]; 8.4, [9]; 11.8, [8]; 16, [9]). 2 pts had DLTs (11.8 and 16.0 mg; both Grade 3 acneiform rash); MTD has not been reached. Pts received a median of 2 cycles (range 1-11, 6 pts ≥6 cycles). Safety and PK data are shown in the table. Maximum inhibition (Emax) of ERK phosphorylationin peripheral blood lymphocytes ranged from 21-95% (TAK-733; 0.2-16 mg QD), median Emax were 63%, 78%, and 92% at 8.4, 11.8, and 16 mg, respectively. In 32 evaluable pts, 1 pt (16 mg dose) with melanoma (BRAF L597R) had partial response confirmed at cycle 6 (RECIST v1.1) and is still on treatment at cycle 8; 12 pts had a best response of stable disease.


These preliminary data indicate that TAK-733 is generally well tolerated and pharmacodynamically active with signs of anti-tumor activity in pts with advanced non-hematologic malignancies. Dose escalation is continuing to determine the MTD.

AEs, NCI-CTCAE v4.0 N = 44
Drug-related AE, n (%) 37 (84)
Dermatitis acneiform 19 (43)
Diarrhoea 8 (18)
Grade ≥3 drug-related AE, n (%) 7 (16)
Dermatitis acneiform 2 (5)
Creatine phosphokinase evaluation 2 (5)
PK data N = 41
Tmax, h 3
T1/2, h 53


P.M. LoRusso: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Research Funding (Millennium Pharmaceuticals Inc.).

A. Ribas: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.).

J.A. Sosman: Consultancy or advisory board (Millennium Pharmaceuticals Inc.), Honoraria (Millennium Pharmaceuticals Inc.).

B. Chmielowski: Consultancy within past 2 years (GSK, Genentech, Prometheus, CytRx, Morphotek). Membership on Board of Directors, Speakers Bureau, Advisory Committee (BMS, Genentech, Prometheus).

P. Lipman: Employment (Millennium Pharmaceuticals Inc.).

X. Zhou: Employment (Millennium Pharmaceuticals Inc.).

V. Bozón: Employment (Millennium Pharmaceuticals Inc.).

All other authors have declared no conflicts of interest.