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Clin Cancer Res. 2017 Sep 1;23(17):5015-5023. doi: 10.1158/1078-0432.CCR-16-2888. Epub 2017 May 10.

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.

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Massachusetts General Hospital, Boston, Massachusetts.
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
Yale University, New Haven, Connecticut.
Mary Crowley Cancer Research Center, Dallas, Texas.
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
Massachusetts General Hospital, Boston, Massachusetts.
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Investigative Clinical Oncology, Fondazione Del Piemonte Per L'Oncologia, Candiolo Cancer Institute, Candiolo, Italy.
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.


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.

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