A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.
View/ Open
Date
2017-09ICR Author
Author
Juric, D
de Bono, JS
LoRusso, PM
Nemunaitis, J
Heath, EI
Kwak, EL
Macarulla Mercadé, T
Geuna, E
Jose de Miguel-Luken, M
Patel, C
Kuida, K
Sankoh, S
Westin, EH
Zohren, F
Shou, Y
Tabernero, J
Type
Other
Metadata
Show full item recordAbstract
Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. Experimental Design: Seventy-one patients received oral TAK-117 once daily [100-300 mg ( n = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg ( n = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg ( n = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. Results: TAK-117 once-daily dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg once daily). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg once daily. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of once-daily/MWF/MTuW patients. TAK-117 (100-1,200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were approximately 4 times greater than with 150 mg once daily. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (once daily/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated). Conclusions: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus once-daily dosing. Although the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted. Clin Cancer Res; 23(17); 5015-23. ©2017 AACR .
Collections
Subject
Humans
Neoplasms
Imidazoles
Morpholines
Pyridines
Benzoxazoles
Protein Kinase Inhibitors
Neoplasm Staging
Dose-Response Relationship, Drug
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Class I Phosphatidylinositol 3-Kinases
Research team
Prostate Cancer Targeted Therapy Group
Language
eng
License start date
2017-09
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (17), pp. 5015 - 5023