Related Experiment Video
Updated: Mar 2, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with
Dejan Juric1, Johann S de Bono2, Patricia M LoRusso3
1Massachusetts General Hospital, Boston, Massachusetts. juric.dejan@mgh.harvard.edu.
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.
Insights
Intermittent dosing of TAK-117, a PI3Kα inhibitor, showed an acceptable safety profile and higher drug exposure compared to daily administration. Further research is recommended for combination therapies in advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is frequently dysregulated in cancer.
- TAK-117 is an investigational inhibitor targeting the PI3Kα isoform, a key player in this pathway.
Purpose of the Study:
- To assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117.
- To compare different oral dosing schedules (once daily vs. intermittent) of TAK-117 in patients with advanced solid tumors.
Main Methods:
- A Phase 1 dose-escalation study using a 3+3 design in 71 patients with advanced solid tumors.
- TAK-117 was administered orally once daily or three days per week (MWF or MTuW) in 21-day cycles.
- Safety, MTD, pharmacokinetic parameters, pharmacodynamic markers (skin pS6 expression), and antitumor responses were evaluated.
Main Results:
- Once-daily dosing was limited by dose-limiting liver enzyme elevations (ALT/AST), establishing a narrow therapeutic dose range.
- Intermittent dosing (MWF/MTuW) allowed for higher doses and increased total weekly drug exposure without dose-limiting liver toxicities.
- Pharmacokinetic analysis revealed dose-proportional exposure and a half-life of approximately 11 hours.
- Pharmacodynamic effects (pS6 suppression) were observed, and preliminary antitumor activity included partial responses and stable disease in PIK3CA-mutated tumors.
Conclusions:
- Intermittent dosing of TAK-117 offers an improved safety profile and higher systemic exposure compared to once-daily administration.
- While single-agent activity may be limited, TAK-117 warrants further investigation in combination therapies for advanced solid tumors.
