A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3K alpha Isoform Inhibitor, in Patients with Advanced Solid Malignancies

作者：Juric Dejan^*; de Bono Johann S; LoRusso Patricia M; Nemunaitis John; Heath Elisabeth I; Kwak Eunice L; Macarulla Mercade Teresa; Geuna Elena; de Miguel Luken Maria Jose; Patel Chirag; Kuida Keisuke; Sankoh Serap; Westin Eric H; Zohren Fabian; Shou Yaping; Tabernero Josep

来源：Clinical Cancer Research, 2017, 23(17): 5015-5023.

DOI：10.1158/1078-0432.CCR-16-2888

Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3K alpha-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.

• 出版日期2017-9-1