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

Abstract

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. .

Pivotal Considerations for Optimal Deployment of Healthy Volunteers in Oncology Drug Development

“…Evaluation by a pharmaceutical company of the feasibility of conducting clinical pharmacology studies in NHVs instead of patients with cancer requires cross‐functional collaboration ( Figure 2). An example of such a systematic evaluation was illustrated via an overview of considerations evaluated by Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, surrounding the decision to conduct clinical pharmacology studies of TAK‐117, a small molecule, potent and selective oral PI3Kα isoform inhibitor, in NHVs, in order to characterize the sources of high PK variability observed in an FIH study in patients with cancer (http://ClinicalTrials.gov: NCT01449370) …”

“…The FIH dose‐escalation study was conducted in 71 patients with advanced solid tumors. Its objectives were to evaluate the safety, maximum tolerated dose (MTD), PK, pharmacodynamic, and preliminary antitumor activity of TAK‐117 using the conventional 3 + 3 design . Several once‐daily and intermittent dosing regimens were evaluated in 21‐day cycles until disease progression or unacceptable toxicities.…”

“…Millennium Pharmaceuticals, Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, surrounding the decision to conduct clinical pharmacology studies of TAK-117, a small molecule, potent and selective oral PI3Kα isoform inhibitor, in NHVs, in order to characterize the sources of high PK variability observed in an FIH study in patients with cancer (Clini calTr ials.gov: NCT01449370). 39 The FIH dose-escalation study was conducted in 71 patients with advanced solid tumors. Its objectives were to evaluate the safety, maximum tolerated dose (MTD), PK, pharmacodynamic, and preliminary antitumor activity of TAK-117 using the conventional 3 + 3 design.…”

“…Its objectives were to evaluate the safety, maximum tolerated dose (MTD), PK, pharmacodynamic, and preliminary antitumor activity of TAK-117 using the conventional 3 + 3 design. 39 Several once-daily and intermittent dosing regimens were evaluated in 21-day cycles until disease progression or unacceptable toxicities. Although TAK-117 plasma exposures were found to be generally dose-proportional over the 100-1,200 mg dose range evaluated, intersubject variability was high (area under the curve to infinity (AUC inf ) percentage of coefficient of variation of 39-85%).…”

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…58 In the first-in-human dose-escalation study of MLN117, doses of 200-900 mg suppressed phosphorylation of 4E-BP1 and S6 in the skin by up to ∼100% and 70%-90%, respectively, at ∼3 hours post single dose. 59 However, evaluation of target inhibition in the tumor itself has not yet been reported for this drug.…”