TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

Autor:	Burris, Howard, Kurkjian, C., Hart, L., Pant, S., Murphy, P., Jones, S., Neuwirth, R., Patel, C., Zohren, F., Infante, J., Burris, Howard A 3rd, Kurkjian, C D, Murphy, P B, Jones, S F, Patel, C G, Infante, J R
Předmět:	PACLITAXEL TRASTUZUMAB CANCER patients KINASE inhibitors PHARMACOKINETICS ANTINEOPLASTIC agents THERAPEUTICS CLINICAL trials COMPARATIVE studies DRUG dosage DOSE-effect relationship in pharmacology DRUG toxicity HETEROCYCLIC compounds RESEARCH methodology MEDICAL cooperation PROTEINS RESEARCH TUMORS EVALUATION research TREATMENT effectiveness CHEMICAL inhibitors
Zdroj:	Cancer Chemotherapy & Pharmacology; Aug2017, Vol. 80 Issue 2, p261-273, 13p
Abstrakt:	Purpose: This 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.Methods: Sixty-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.Results: TAK-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.Conclusion: TAK-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 Identifier: NCT01351350. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink