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- Title
TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.
- Authors
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
- Abstract
<bold>Purpose: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.<bold>Gov Identifier: </bold>NCT01351350.
- Subjects
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
- Publication
Cancer Chemotherapy & Pharmacology, 2017, Vol 80, Issue 2, p261
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-017-3343-4