Drug-drug interactions with pioglitazone, losartan, and midazolam and anti-tumor efficacy and safety study of TAS-115 in patients with solid tumors.

PURPOSE: TAS-115 is an oral multi-kinase inhibitor currently under development for the treatment of osteosarcoma and chronic fibrosing interstitial lung diseases with a progressive phenotype. In this study, we evaluated the effect of multiple administrations of TAS-115 on the pharmacokinetic (PK) changes in CYP2C8, CYP2C9, and CYP3A4 substrates, as well as its anti-tumor efficacy and safety in patients with solid tumors. METHODS: Patients received a single oral dose of pioglitazone (CYP2C8 substrate) followed by a cocktail dose of losartan (CYP2C9 substrate) and midazolam (CYP3A4 substrate), both before and during the period of multiple oral TAS-115 doses to evaluate the impact on individual drug PKs with and without TAS-115. Patients who met the inclusion criteria received multiple administrations of TAS-115 in a 21-day cycle (5 days on, 2 days off) until the treatment discontinuation criteria were met. RESULTS: TAS-115 increased the area under the plasma concentration-time curve from time 0 to infinity (AUCinf) for pioglitazone, losartan, midazolam and 1-hydroxymidazolam by a geometric mean ratio (GMR) of 1% (90% confidence interval: 0.91–1.12), 11% (0.97–1.26), -7% (0.84–1.03) and 5% (0.95–1.15), respectively. No additional or unexpected toxicities occurred. The overall response rate (ORR) was 6.3% and the disease control rate (DCR) was 37.5% for patients with solid tumors, including ORR of 25% and DCR of 50% for four patients with osteosarcoma. CONCLUSION: TAS-115 had a limited impact on drug-drug interactions mediated by CYP2C8, CYP2C9, and CYP3A4. Further, the antitumor efficacy and safety profile of TAS-115 suggest its potential as a treatment option for osteosarcoma. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: jRCT2031210372, October 11, 2021.