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|Ref Type||Journal Article|
|Authors||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|
|Title||A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2017 Sep 01|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Serabelisib||INK1117|TAK-117|MLN-1117|MLN1117||PIK3CA inhibitor 18||Serabelisib (MLN1117) selectively inhibits PI3K alpha kinase, including mutations of PIK3CA, and therefore, targets the PI3K/Akt/mTOR pathway with potentially less toxicity than pan-PI3K inhibitors (PMID: 28490463, PMID: 30168905).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA mutant||breast cancer||predicted - sensitive||Serabelisib||Case Reports/Case Series||Actionable||In a Phase I trial, MLN1117 (INK1117) treatment resulted in partial response in 3 patients with breast cancer harboring PI3CA mutations (PMID: 28490463; NCT01449370).||28490463|
|PIK3CA mutant||stomach cancer||predicted - sensitive||Serabelisib||Case Reports/Case Series||Actionable||In a Phase I trial, MLN1117 (INK1117) treatment resulted in a partial response in one patient with gastric cancer harboring a PIK3CA mutation (PMID: 28490463; NCT01449370).||28490463|