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Futibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18–55 years. In part 1, 20 participants received digoxin (P‐gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10‐day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3‐day washout, quinidine (P‐gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment‐emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P‐gp or BCRP substrates and that the effect of P‐gp inhibition on futibatinib PK is not clinically relevant. [ABSTRACT FROM AUTHOR]

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, was recently approved for FGFR2 rearrangement–positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14C‐futibatinib single oral 20‐mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half‐life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine‐conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14C‐futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1‐aminobenzotriazole (a pan‐cytochrome P450 inhibitor), and glutathione‐ and cysteine‐conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O‐desmethylation and glutathione conjugation, with cytochrome P450 enzyme‐mediated desmethylation as the main oxidation pathway. 14C‐futibatinib was well tolerated in this Phase 1 study. [ABSTRACT FROM AUTHOR]

Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1–4 inhibitor, is being evaluated for FGFR‐aberrant tumors. Two open‐label phase 1 studies evaluated the effects of high‐fat, high‐calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single‐dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N = 17), subjects received futibatinib under fed and fasted conditions, separated by a 7‐day washout. In the PPI study (N = 20), subjects received futibatinib alone, underwent a 2‐day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration–time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%–98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P <.0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid‐reducing agents. [ABSTRACT FROM AUTHOR]

Futibatinib, a fibroblast growth factor receptor (FGFR) 1–4 inhibitor, is being investigated for FGFR‐aberrant tumors. A 4‐period, crossover, phase 1 thorough QT/QTc study compared effects on Fridericia heart rate–corrected QT (QTcF) interval of single doses of futibatinib 20 and 80 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin (positive control) in healthy subjects. The study objective was to assess the time‐matched difference in change from baseline in QTcF (ddQTcF) between futibatinib and placebo. In addition, changes from baseline in QTcF and other electrocardiogram (ECG) parameters, pharmacokinetics, ECG morphology, and safety were assessed. Forty‐eight subjects were randomized. ddQTcF upper limits of 2‐sided 90%CIs remained <10 milliseconds (clinical threshold) for both futibatinib doses at all time points (range, 2.0–4.5 milliseconds). Assay sensitivity was demonstrated by lower limits of 2‐sided 97.5%CIs of the dQTcF difference between moxifloxacin and placebo of >5 milliseconds. Futibatinib exposure increased in a dose‐dependent manner, and no significant relationship was detected between plasma futibatinib concentration and ddQTcF. There were no significant effects on heart rate, other ECG parameters, or ECG morphology. No serious adverse events occurred. Futibatinib did not prolong QTcF or affect other cardiac measures at therapeutic or supratherapeutic doses. [ABSTRACT FROM AUTHOR]

PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations. [ABSTRACT FROM AUTHOR]

Tegafur (FT) is a 5-fluorouracil (5-FU) prodrug that has been clinically used for various cancer chemotherapies. The following metabolites of FT were identified in patients: 5-FU, fluoro-beta-alanine, and gamma-butyrolactone (GBL) and its acidic form, gamma-hydroxybutyrate (GHB). GBL/GHB, which is probably generated from the furan ring of FT, inhibits tumor cell angiogenesis, contributing to the antitumor effect of FT-based therapies. In the present study, we identified the metabolites formed from the furan ring of FT by CYP2A6 and thymidine phosphorylase (TPase) using 2,4-dinitrophenylhydrazine derivatization procedures and clarified the metabolic pathway of FT to GBL/GHB. Succinaldehyde (SA) and 4-hydroxybutanal (4-OH-BTL) were produced as the metabolites because of the cleavage of the furan ring of FT during its conversion to 5-FU in cDNA-expressed CYP2A6 and purified TPase, respectively; however, GBL/GHB was hardly detected in cDNA-expressed CYP2A6 and purified TPase. GBL/GHB was formed after human hepatic microsomes or cDNA-expressed CYP2A6 mixed with cytosol were incubated with FT. Furthermore, 4-OH-BTL was converted to GBL/GHB in the microsomes and cytosol. These results suggest that GBL/GHB is generated from FT through the formation of SA and 4-OH-BTL but not directly from FT. Furthermore, the amount of 5-FU and GBL/GHB formed in the hepatic S9 was markedly decreased in the presence of a CYP2A6 inhibitor, suggesting that GBL/GHB may be mainly generated through the CYP2A6-mediated formation of SA.