Phase 1 Dose-Escalation Trial of the Investigational Hedgehog (HH) Pathway Inhibitor Tak-441 in Patients with Advanced Solid Tumors

ABSTRACT Background Dysregulation of the Hh pathway is a principal event in the carcinogenesis of multiple tumor types, including basal cell carcinoma. TAK-441 is an investigational, orally-available inhibitor of the G protein-coupled receptor Smoothened, a component of the Hh signalling cascade. Methods This study (NCT01204073) was designed to determine safety, maximum tolerated dose (MTD) and maximum feasible dose (MFD) in patients with advanced solid tumors. Cycles consisted of 3 weeks continuous dosing, with a single-dose cycle 1 lead-in, followed by 7 d pharmacokinetics (PK). Dose escalation (DE) proceeded in a modified 3 + 3 fashion. Radiographic tumor assessments were performed after cycles 2, 4, and every 4 cycles thereafter. Results Thirty-two patients were enrolled in the DE phase, median age 59 y (range 28–82), and treated with doses from 50–1600 mg daily. TAK-441 concentrations were quantifiable in plasma after the starting 50 mg dose, with total exposure increasing dose-proportionally to 800 mg. Maximum plasma concentration typically was reached 3 h post-dose. The median terminal disposition half-life was 15 h (range 6–35 h). DLTs of Gr 3 fatigue and muscle spasms were observed in 1 pt at the 1600 mg dose. Six subjects discontinued due to an adverse event (AE) including a patient who suffered a fatal cerebral hemorrhage in cycle 4 related to 50 mg TAK-441. Most common treatment-emergent AEs were muscle spasms (44%), dysguesia (41%), nausea (41%), fatigue (38%) and constipation (28%). The MFD is 1600 mg and the MTD has not been reached. Four patients remained on trial for u003e10 cycles, and 3 patients continue on treatment. Response and PK/PD data will be presented. Conclusions TAK-441 was well-tolerated up to an MFD of 1600 mg taken once daily. A dose expansion cohort has been initiated at 800 mg in patients with untreated basal cell carcinoma. Disclosure S.G. Eckhardt: Consultancy, Research funding and Speakers Bureau/Advisory Committee for Millennium/Takeda. S. Kuan: Employment with Millennium Pharmaceuticals, Inc. J. Yu: Employment and consultancy for Millennium. L.S. Rosen: Research support from Millennium. All other authors have declared no conflicts of interest.