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Τετάρτη 10 Μαΐου 2017

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

Purpose: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. <p>Experimental Design: Seventy-one patients received oral TAK-117 once daily (QD, 100-300 mg [n = 24]), or 3 days per week (Mon-Wed-Fri [MWF], 200-1200 mg [n = 27]; Mon-Tue-Wed [MTuW], 200-900 mg [n = 20]), in 21-day cycles. Dose escalation proceeded via a 3+3 design.</p> <p>Results: TAK-117 QD 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 QD). 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 QD. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of QD/MWF/MTuW patients. TAK-117 (100-1200 mg) exhibited moderately fast oral absorption, a generally dose-proportional increase in exposure, and plasma half-life of ~11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were ~four times greater than with 150 mg QD. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (QD/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).</p> <p>Conclusion: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus QD dosing. While the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.



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