LAUSR

PurposeThis phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.MethodsSixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1.ResultsTAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months.ConclusionTAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors.Clinicaltrials.gov identifierNCT01351350.