TY - JOUR
T1 - A first-in-human, Phase I, dose-escalation study of TAK-117, A selective PI3Ka isoform inhibitor, in patients with advanced solid malignancies
AU - Juric, Dejan
AU - De Bono, Johann S.
AU - LoRusso, Patricia M.
AU - Nemunaitis, John
AU - Heath, Elisabeth I.
AU - Kwak, Eunice L.
AU - Mercade, Teresa Macarulla
AU - Geuna, Elena
AU - De Miguel-Luken, Maria Jose
AU - Patel, Chirag
AU - Kuida, Keisuke
AU - Sankoh, Serap
AU - Westin, Eric H.
AU - Zohren, Fabian
AU - Shou, Yaping
AU - Tabernero, Josep
PY - 2017/9/1
Y1 - 2017/9/1
N2 - © 2017 American Association for Cancer Research. Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-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 doselimiting 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.
AB - © 2017 American Association for Cancer Research. Purpose: To evaluate the safety, MTD, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Ka-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 doselimiting 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.
U2 - 10.1158/1078-0432.CCR-16-2888
DO - 10.1158/1078-0432.CCR-16-2888
M3 - Article
VL - 23
SP - 5015
EP - 5023
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 17
ER -