TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in
Howard A Burris1,2, C D Kurkjian3,4, L Hart3,5
1Sarah Cannon Research Institute, 250 25th Avenue North, #100, Nashville, TN, 37203, USA. Howard.Burris@scresearch.net.
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.
Insights
This Phase I trial of TAK-228 plus paclitaxel showed promising antitumor activity in advanced solid tumors. The investigational drug TAK-228 demonstrated a manageable safety profile, supporting further research in combination therapies.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Target of Rapamycin (TOR) signaling is implicated in various cancers.
- Developing novel inhibitors like TAK-228 is crucial for advancing cancer therapy.
Purpose of the Study:
- To assess the safety, pharmacokinetics, and antitumor effects of TAK-228 combined with paclitaxel.
- To evaluate the addition of trastuzumab to the TAK-228 and paclitaxel regimen.
Main Methods:
- Phase I, dose-escalation study of TAK-228 in 67 patients with advanced solid tumors.
- TAK-228 administered on three different schedules with paclitaxel, and in an expansion phase with trastuzumab.
- Modified 3+3 design used for dose escalation based on dose-limiting toxicities.
Main Results:
- TAK-228 showed dose-dependent pharmacokinetics with paclitaxel, with no significant PK differences based on administration timing relative to paclitaxel.
- Maximum tolerated dose of TAK-228 established; common toxicities included neutropenia and diarrhea.
- Preliminary antitumor activity observed, with partial responses and durable stable disease in evaluable patients.
Conclusions:
- TAK-228 exhibits a safety profile consistent with TORC inhibitors and shows preliminary antitumor activity.
- The combination of TAK-228 with paclitaxel, with or without trastuzumab, warrants further investigation in advanced solid tumors.
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