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

Abstract

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.

Figure 1.

Pharmacokinetic analyses of TAK-117: A, Mean TAK-117 plasma concentration-time profile by dose level on day 1 of cycle 1. B and C, Dose proportionality plot of TAK-117 dose versus AUC_0–24 h (B); and simulated TAK-117 plasma concentration-time profiles over a dosing week for the once-daily and intermittent dosing schedules (C). AUC_{0–24 h}, area under the TAK-117 plasma concentration-time curve from 0 to 24 hours; C_avg, average TAK-117 plasma concentration; Cl, confidence interval; QD, once daily.

Figure 2.

Pharmacodynamic effects of TAK-117: A and B, Box-and-whisker plot showing changes from baseline in pS6 expression in skin biopsies [A; boxes, interquartile distance (Q1–Q3); bars, median; whiskers, 10th and 90th percentiles; circles, observations outside 90% distribution interval]; and representative images of tumor biopsies from patients dosed at 200 mg on the intermittent schedules showing decreased pS6 expression (B; indicated by the IHC H-score provided below each image). Scale bar, 200 mmol/L.

Figure 3.

Treatment duration and response in patients treated with TAK-117 100 to 1,200 mg. Med dur, median duration of clinical benefit; NSCLC, non-small cell lung cancer; PD, progressive disease; QD, once daily; SD, stable disease.