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|| Drug Development
A.A. Adjei1, P. Lorusso2, A. Ribas3, J.A. Sosman4, G.K. Dy5, B. Chmielowski6, P. Lipman7, X. Zhou8, E. Gangolli9, V. Bozón10
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.Methods
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.Results
As of March 16, 2012, 44 pts median age 58 (range 24 − 75) and 50% male, received TAK-733 (dose mg, [n]: 0.2, ; 0.4, ; 0.8, ; 1.6, ; 3.2, ; 4.4, ; 6, ; 8.4, ; 11.8, ; 16, ). 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.Conclusions
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)|
|Grade ≥3 drug-related AE, n (%)||7 (16)|
|Dermatitis acneiform||2 (5)|
|Creatine phosphokinase evaluation||2 (5)|
|PK data||N = 41|
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.