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

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. Seventy-one patients received oral TAK-117 once daily [100-300 mg ( = 24)] or 3 days...

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Bibliographic Details
Published in:Clinical cancer research 2017-09, Vol.23 (17), p.5015-5023
Main Authors: Juric, Dejan, de Bono, Johann S, LoRusso, Patricia M, Nemunaitis, John, Heath, Elisabeth I, Kwak, Eunice L, Macarulla Mercadé, Teresa, Geuna, Elena, Jose de Miguel-Luken, Maria, Patel, Chirag, Kuida, Keisuke, Sankoh, Serap, Westin, Eric H, Zohren, Fabian, Shou, Yaping, Tabernero, Josep
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alanine
Anticancer properties
Antitumor activity
Aspartate aminotransferase
Cancer
Class I Phosphatidylinositol 3-Kinases - genetics
Constraining
Dosage
Dose-Response Relationship, Drug
Experimental design
Exposure
Female
Humans
Hyperglycemia
Inhibitors
Male
Middle Aged
Neoplasm Staging
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
Patients
Pharmacodynamics
Pharmacokinetics
Pharmacology
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - adverse effects
Quality
Safety
Skin
Solid tumors
Tumors
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Summary: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. Seventy-one patients received oral TAK-117 once daily [100-300 mg ( = 24)] or 3 days per week [Monday-Wednesday-Friday (MWF), 200-1,200 mg ( = 27); Monday-Tuesday-Wednesday (MTuW), 200-900 mg ( = 20)], in 21-day cycles. Dose escalation proceeded via a 3 + 3 design. 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 mutated). 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. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-16-2888