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

Abstract

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.

• Authors: Howard A Burris 3rd, C D Kurkjian, L Hart, S Pant, P B Murphy, S F Jones, R Neuwirth, C G Patel, F Zohren, J R Infante
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 80 Issue 2 Pg. 261-273 (Aug 2017) ISSN: 1432-0843 [Electronic] Germany
• PMID: 28601972 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• Benzoxazoles
• Multiprotein Complexes
• Pyrimidines
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• sapanisertib
• Trastuzumab
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Benzoxazoles (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Middle Aged
• Multiprotein Complexes (antagonists & inhibitors)
• Neoplasms (drug therapy, pathology)
• Paclitaxel (administration & dosage)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Trastuzumab (administration & dosage)
• Treatment Outcome
• Young Adult