Abstract
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.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00280-025-04855-9.
Keywords: TAS-115, Pamufetinib, Drug–drug interactions, Cytochrome P450, Cocktail, Osteosarcoma
Introduction
Despite significant recent advances in cancer treatment, cancer remains the second leading cause of death worldwide, resulting in 10 million deaths in 2020 [1]. The number of cancer patients reached 19.3 million, a figure expected to increase to 30.2 million by 2040 [2]. These statistics underscore the urgent need for improved cancer treatments.
TAS-115 (International Nonproprietary Name [INN]: pamufetinib) is a novel oral multi-kinase inhibitor that acts by inhibiting targets such as the Met proto-oncogene (MET), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and colony-stimulating factor 1 receptor (CSF1-R) in an adenosine triphosphate (ATP)-competitive manner [3–14]. TAS-115 has demonstrated promising preliminary antitumor efficacy in Phase 1 and Phase 2 studies in patients with solid tumors [15], osteosarcoma [16], and prostate cancer with bone metastases [17]. In addition, in a Phase 2a study in patients with idiopathic pulmonary fibrosis, TAS-115 showed a promising effect in slowing the decline of percent predicted forced vital capacity (%FVC) [18, 19]. Currently, a pivotal Phase 3 study in patients with osteosarcoma is ongoing, and a Phase 2 study has been completed in patients with chronic fibrosing interstitial lung diseases with a progressive phenotype.
A comprehensive assessment of drug-drug interactions (DDI) is a key component in the development of TAS-115, allowing for the optimization of drug therapy for individual patients. In vitro studies revealed that TAS-115 reversibly inhibits CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A (midazolam 1’-hydroxylation), and CYP3A (testosterone 6β-hydroxylation) with IC50 values of 6.03, 0.563, 2.03, 4.23, 4.49, and 3.05 µmol/L, respectively. TAS-115 also demonstrated a time-dependent inhibitory effect on CYP3A with a maximum inactivation rate constant of 0.0650 min− 1, and the concentration of the inhibitor required to achieve 50% of the maximum inactivation rate was 28.5 µmol/L (unpublished inhouse data). We initially investigated potential DDI of TAS-115 at a maximum clinical dose of 250 mg/day, using basic models outlined in the guideline on drug interaction for drug development and appropriate provision of information [20], reflecting current development settings. Our findings revealed that the possibility of potential clinical DDI cannot be ruled out due to a reversible inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19 in the liver and both reversible and time-dependent inhibitions of CYP3A in the gastrointestinal tract and liver.
In this clinical study, we excluded healthy adults from the study population, focusing on patients with advanced solid tumors who had no standard therapy available. This approach allowed us to evaluate the effects on DDI as well as the efficacy and safety of multiple administrations of the maximum clinical dose of TAS-115 for patients with solid tumors who had few effective treatment options. Additionally, our overall evaluation method offers a valuable example of a clinical protocol that minimizes patient burden during the DDI evaluation period while ensuring potential clinical benefits and safety.
Materials and methods
TAS-115 mini-tablets
Round, film-coated, mini-tablets containing 50 mg TAS-115 (drug substance) as free base. Each tablet contains the following inactive ingredients: hydroxypropyl-β-cyclodextrin, light anhydrous silicic acid, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and yellow ferric oxide.
Pioglitazone
ACTOS® Tablets 15 was used as pioglitazone.
Losartan
Losartan potassium tablets 25 mg [“TEVA”] was used as losartan.
Midazolam
BUCCOLAM® oromucosal solution 2.5 mg was used as midazolam. We prepared an oral solution by diluting BUCCOLAM oromucosal solution with 5% dextrose injection solution. First, we combined the entire content of the BUCCOLAM oromucosal solution with 20 mL of 5% dextrose injection solution in a dosing bottle, ensuring the mixture did not stick to the lid. To prevent buccal absorption and ensure that BUCCOLAM oromucosal solution was primarily absorbed through the gastrointestinal tract, patients were then instructed to swallow the solution immediately. Next, we added another 20 mL of 5% dextrose injection solution to the same bottle, mixed again, and the patient swallowed this solution as well to ensure complete transfer to the stomach.
Patients: major eligibility criteria
Eligible patients were those with solid tumors aged 20 years or older (or with malignant bone tumors aged 15 years or older) who were refractory or intolerant to standard treatments, or for whom no appropriate treatments were available. All patients were required to provide informed consent. Detailed inclusion and exclusion criteria are described in the Supplementary material section.
Sample size
The target sample size for this study was 18 patients. Assuming that the intra-individual coefficient of variation of the pharmacokinetic (PK) parameters of the cytochrome P450 (CYP) substrates was 30%, when the true ratios of the geometric mean of the PK parameters of a single CYP substrate before and after coadministration of TAS-115 were 1.25 and 1.5, the probability that the lower limit of the 90% confidence interval (CI) of the ratio of the geometric mean obtained from 16 patients exceeds 1 was 66% and 98%, respectively. Although no hypothesis testing was specified in determining the primary objective of this study, it was considered reasonable to set a sample size of approximately 16 patients, in order to preserve an acceptable threshold for detecting an effect. We decided to enroll 18 patients, to allow for possible dropouts.
Rationale for dosing plan of marker substrates in this study
The Inje cocktail, which contains losartan and midazolam, has been established as a substrate cocktail [21]. However, because there have been no studies using cocktail substrates containing pioglitazone, we planned to administer pioglitazone on a separate day. To maximize the time-dependent inhibitory effect of TAS-115 on CYP3A, we administered midazolam, a CYP3A substrate, on Day 5 of once-daily TAS-115 administration. Therefore, we evaluated the interaction of TAS-115 with pioglitazone on Day 4 of TAS-115 administration, and with losartan and midazolam on Day 5.
Study design
This multicenter, open-label, single-arm study evaluated the effect of multiple oral doses of TAS-115 on the PKs of single oral doses of pioglitazone (CYP2C8 substrate), losartan (CYP2C9 substrate), and midazolam (CYP3A substrate) in patients with solid tumors. The study was conducted in Japan. The study comprised two phases: a DDI evaluation period and a continuous administration period. During the DDI evaluation period, patients received a single oral dose of pioglitazone (CYP2C8 substrate) followed by the cocktail dosing of losartan (CYP2C9 substrate) and midazolam (CYP3A4 substrate) both before and during multiple oral doses of TAS-115 to evaluate the impact on individual drug PKs with and without TAS-115. Patients meeting the continuous administration period criteria proceeded to the continuous administration period, where TAS-115 was administered in a 21-day cycle (5 days on, 2 days off) until treatment discontinuation criteria were met. The study design is shown in Fig. 1.
Fig. 1.
An overview of the dosing schedule. Day 1 was defined as the first day of TAS-115 administration. F/U follow-up. Cy Cycle: a 21-day cycle (5 days on, 2 days off)
DDI Evaluation Period: Following screening, an eligible patient was hospitalized the day before the first dose of pioglitazone was administered. Day 1 was defined as the first day of TAS-115 administration. The patient received pioglitazone 15 mg on Day − 3 and Day 4 (30 min after TAS-115 dosing) and losartan 25 mg and midazolam 2.5 mg on Day − 2 and Day 5 (30 min after TAS-115 dosing) to evaluate individual drug PKs. The patient received multiple doses of TAS-115 at 250 mg once daily from Day 1 to Day 5, which was the planned maximum clinical daily dose. All treatments were performed in the fasted state. The patient was to be discharged when no clinically significant findings were found by the specified tests on Day 8 (acceptable time window, − 2 days). Concomitant use of medications or foods that may affect the evaluation of DDI (e.g., agents known to inhibit or induce CYP2C8, CYP2C9, or CYP3A) was prohibited during the DDI evaluation period.
Continuous administration period: If a patient wished to continue treatment with TAS-115 and met the continuous administration period criteria, he or she started to receive TAS-115 within 14 days after the tests at the end of treatment in the DDI evaluation period. Patients received 250 mg TAS-115 in the fasted state for 5 consecutive days starting on Day 1 of each 21-day cycle, followed by 2 days off, in repeated cycles. Patients continued receiving TAS-115 until the criteria for discontinuation of study treatment were met.
Outcomes
Primary endpoint
PK parameters of pioglitazone, losartan, and midazolam (maximum plasma concentration [Cmax], area under the plasma concentration-time curve up to the last observable concentration [AUClast], area under the plasma concentration-time curve from time 0 to infinity [AUCinf]).
Secondary endpoints
PK parameters of pioglitazone, losartan, and midazolam (time to maximum plasma concentration [Tmax], terminal elimination rate constant [λz], terminal elimination half-life [T1/2], mean residence time [MRT], oral clearance [CL/F], apparent volume of distribution [Vz/F]) and 1’-hydroxymidazolam (Cmax, AUClast, AUCinf, Tmax, λz, T1/2, metabolite-to-parent molar ratio for maximum plasma concentration [MRCmax], metabolite-to-parent molar ratio for area under the plasma concentration-time curve up to the last observable concentration [MRAUClast], metabolite-to-parent molar ratio for area under the plasma concentration-time curve from time 0 to infinity [MRAUCinf]).
PK parameters of TAS-115.
Incidence and severity of adverse events (AEs), changes in vital signs and laboratory values, electrocardiogram (ECG) changes.
Overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) evaluated based on the assessment of the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to grade the severity of AEs.
Bioanalytical methods
Blood samples were collected for PK analysis from Day − 3 to Day 2 and from Day 4 to Day 6. Detailed sampling points are shown in Supplementary Table S1. The plasma concentrations of pioglitazone, losartan, midazolam, 1’-hydroxymidazolam, and TAS-115 were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Stable isotope-labeled internal standards of each analyte were used. Samples extracted by solid-phase extraction (for pioglitazone, losartan, midazolam, and 1’-hydroxymidazolam) and deproteinization (for TAS-115) were injected onto C18 reverse-phase columns, before detection by mass spectrometers (API 400 or Triple Quad 5500, AB SCIEX). The calibration ranges were 5–2000 ng/mL for pioglitazone, 1–1000 ng/mL for losartan, 0.02–50 ng/mL for midazolam and 1’-hydroxymidazolam, and 10–10,000 ng/mL for TAS-115. Within- and between-rum precision were ≤ 6.4% and ≤ 6.9%, respectively, for pioglitazone, ≤ 11.7% and ≤ 10.0%, respectively, for losartan, ≤ 4.3% and ≤ 6.0%, respectively, for midazolam, ≤ 5.2% and ≤ 5.5%, respectively, for 1’-hydroxymidazolam, and ≤ 3.9% and ≤ 3.6%, respectively, for TAS-115. Within- and between-run accuracy ranged from − 10.8% to 4.8% and from − 3.2% to 0.8%, respectively, for pioglitazone, from − 12.3% to 7.6% and from − 9.3% to 3.8%, respectively, for losartan, from − 6.5% to 4.0% and − 0.2% to 4.0%, respectively, for midazolam, from 3.8% to 6.5% and from 0% to 5.3%, respectively, for 1’-hydroxymidazolam, and from − 8.2% to 0.9% and − 4.3% to −0.5%, respectively, for TAS-115.
Statistical methods
PK parameters for pioglitazone, losartan, midazolam, 1’-hydroxymidazolam, and TAS-115 were estimated using non-compartmental methods. Log-transformed PK parameters (Cmax, AUClast, AUCinf) were analyzed using a linear mixed-effects model with treatment as a fixed effect and patient as a random effect using Phoenix® WinNonlin® software version 8.1 (Certara, LP, Princeton, NJ, USA). Geometric least squares mean ratios and 90% CI values were calculated. The linear mixed effect model analyses were performed using SAS software version 9.4 and SAS/STAT software version 15.1 or a later version.
Efficacy evaluation methods
The efficacy values were evaluated using the following definitions. The ORR, DCR, and PFS were evaluated based on the RECIST version 1.1. ORR was defined as the percentage of patients with a best overall response of complete response (CR) or partial response (PR). DCR was defined as the percentage of patients with a best overall response of CR, PR, or stable disease (SD). The PFS was defined as the period from the date of enrollment to the date of confirmation of progressive disease (PD) or the date of death from any cause, whichever came earlier. For patients receiving any subsequent treatment before the diagnosis of PD after the completion of treatment with TAS-115, PFS data was to be censored on the date of the last imaging scan performed before the start of the subsequent treatment. For patients who were alive without diagnosis of PD at the time of analysis, PFS data were censored on the date of the last imaging scan. Overall survival (OS) was evaluated in patients with osteosarcoma. OS was defined as the period from the date of enrollment to the date of death due to any cause. If the patient was alive at the time of analysis, the censoring date was the date of the last follow-up assessment, the date of the last survival follow-up, or the date of any other recorded test or observation, whichever occurred the last.
Safety evaluation methods
All AEs occurring between the first dose of pioglitazone and the end of the safety follow-up period (28 days [acceptable up to + 7 days] after the last dose of TAS-115, pioglitazone, losartan, or midazolam) or the date when any of the criteria for discontinuation of the safety follow-up period are met, whichever comes earlier, were collected. AEs considered by the investigator to be related to TAS-115, pioglitazone, losartan, or midazolam were also collected even if they occurred after the safety follow-up period. The CTCAE version 5.0 was used to grade the severity of AEs.
Compliance with ethical standards
This study was conducted in accordance with the clinical protocol and consensus ethical principles derived from international guidelines including the Good Clinical Practice (GCP) Ordinance, the ethical principles that have their origin in the Declaration of Helsinki, and other applicable laws and regulations.
Consent to participate
The investigator or his/her representative explained the nature of the study to the patient and answered all questions regarding the study. Patients were informed that their participation was voluntary. Patients were required to sign a statement of informed consent that met the requirements of the local regulations and the Institutional Review Board (IRB) or study site. Investigative sites were instructed to obtain written informed consent prior to any study-related assessments or procedures in the study and document the date when the written consent was obtained. The investigator obtaining the informed consent was also instructed to sign the Informed Consent Form (ICF). If the clinical research coordinator provided a supplementary explanation, he or she was to sign the ICF. If there were any amendments during their participation in the study, patients were re-consented to the most current version of the ICF(s). A copy of the ICF(s) was provided to the patient.
Consent to publish
All patients agreed to the secondary use of clinical trial results in academic conferences and papers through the ICF.
Results
Patient disposition
All 18 enrolled patients completed the DDI evaluation period and transitioned to the continuous administration period. During the continuous administration period, all patients met the criteria for discontinuation of the investigational drug and subsequently discontinued the study treatment. The reasons for discontinuation were as follows: AE for one patient, disease progression for 13 patients, and withdrawal of consent for four patients. There were no important protocol deviations related to the inclusion/exclusion criteria, study treatment administration, or prohibited concomitant drugs/therapies.
Demography
All population
The same number of men and women aged 15 to 74 (median 63.5) years old was included in the study. Approximately half of the patients had a medical history, while most patients had active symptoms. The numbers of patients who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 1 were approximately the same. Seventeen patients (94%) had received chemotherapy in one or more settings, including neoadjuvant, adjuvant, or advanced metastatic treatment. The most common cancer types were colon (five patients [27.8%]), osteosarcoma (four patients [22.2%]), followed by pancreas (two patients [11.1%]). The most common histology was adenocarcinoma (nine patients [50.0%]).
Efficacy population
Sixteen out of 18 patients were efficacy evaluable. They consisted of five (31.3%) with colon cancer, four (25.0%) with osteosarcoma and one each (6.3%) with chondrosarcoma, breast cancer, non-small cell lung cancer, pancreatic cancer, duodenal cancer, ovarian cancer, or palate cancer. The two excluded patients could not be assessed because no tumor evaluations were performed after administration of TAS-115. A subpopulation analysis of efficacy was performed for four patients with osteosarcoma. All patients had a PS of 1 and a history of chemotherapy at enrollment. Of these four patients, 3 (75%) had fibroblastic osteosarcoma and one (25%) had osteoblastic osteosarcoma.
Exposure
In the DDI evaluation period, all patients received planned treatments. In the continuous administration period, the median total treatment duration with TAS-115 was 28.5 days. In four patients with osteosarcoma, although the sample size was limited to four patients, longer treatment periods were observed compared with the overall patient population, with the longest treatment period being 27 months (Supplementary Figure S2).
Effect of TAS-115 on Pioglitazone PKs
The mean plasma concentration-time profiles of pioglitazone following a single oral dose of 15 mg pioglitazone with and without coadministration of 250 mg TAS-115 once daily are displayed graphically on linear and semi-log scales in Fig. 2a, respectively. Although the mean plasma concentration peak of pioglitazone was slightly increased when it was administered with TAS-115, the elimination phase appeared to be similar to when pioglitazone was administered alone. Based on the statistical comparisons of natural logarithmically transformed pioglitazone PK parameters post-coadministration with TAS-115, Cmax, AUClast, and AUCinf increased by approximately 24%, 8%, and 1%, respectively, when compared with the administration of pioglitazone alone (Table 1a).
Fig. 2.
Plasma concentration versus time plots. Mean (+ standard deviation) pioglitazone (a), losartan (b), and midazolam (c) plasma concentration–time profiles following a single oral dose of pioglitazone (15 mg) on Day 4 and a cocktail dose of losartan (25 mg) and midazolam (2.5 mg) on Day 5 when administered alone (black solid lines) and when administered with TAS-115 (once-daily 250 mg) (red broken lines), presented in linear (upper panel) and semi-logarithmic (lower panel) scales
Table 1.
Statistical comparison of Cmax, AUClast, and AUCinf for marker drugs with or without TAS-115
| (a) Pioglitazone | ||||||||
|---|---|---|---|---|---|---|---|---|
| PK parameter (unit) | Pioglitazone with TAS-115 | Pioglitazone alone | GMR | 90% CI | Intra- patient |
Inter- patient |
||
| (Lower, Upper) | ||||||||
| Geometric LSM | N | Geometric LSM | N | CV% | CV% | |||
| Cmax (ng/mL) | 789.1 | 18 | 635.1 | 18 | 1.24 | (1.05, 1.47) | 29.1 | 32.9 |
| AUClast (ng·hr/mL) | 6839 | 18 | 6335 | 18 | 1.08 | (0.94, 1.24) | 24.1 | 21.9 |
| AUCinf (ng·hr/mL) | 7787 | 16 | 7710 | 14 | 1.01 | (0.91, 1.12) | 15.9 | 19.6 |
| (b) Losartan | ||||||||
|---|---|---|---|---|---|---|---|---|
| PK parameter (unit) | Losartan with TAS-115 | Losartan alone | GMR | 90% CI | Intra- patient |
Inter- patient |
||
| (Lower, Upper) | ||||||||
| Geometric LSM | N | Geometric LSM | N | CV% | CV% | |||
| Cmax (ng/mL) | 167.1 | 18 | 158.5 | 18 | 1.05 | (0.81, 1.38) | 49.1 | 55.7 |
| AUClast (ng·hr/mL) | 395.9 | 18 | 364.1 | 18 | 1.09 | (0.92, 1.28) | 28.9 | 55.8 |
| AUCinf (ng·hr/mL) | 429.4 | 18 | 388.2 | 18 | 1.11 | (0.97, 1.26) | 23.4 | 56.2 |
| (c-1) Midazolam | ||||||||
|---|---|---|---|---|---|---|---|---|
| PK parameter (unit) | Midazolam with TAS-115 | Midazolam alone | GMR | 90% CI | Intra- patient |
Inter- patient |
||
| (Lower, Upper) | ||||||||
| Geometric LSM | N | Geometric LSM | N | CV% | CV% | |||
| Cmax (ng/mL) | 20.03 | 18 | 21.91 | 18 | 0.91 | (0.82, 1.02) | 18.6 | 47.9 |
| AUClast (ng·hr/mL) | 51.58 | 18 | 55.51 | 18 | 0.93 | (0.84, 1.03) | 17.5 | 62.4 |
| AUCinf (ng·hr/mL) | 52.89 | 18 | 56.78 | 18 | 0.93 | (0.84, 1.03) | 17.9 | 63.5 |
| (c-2) 1’-Hydroxymidazolam | ||||||||
|---|---|---|---|---|---|---|---|---|
| PK parameter (unit) | Midazolam with TAS-115 | Midazolam alone | GMR | 90% CI | Intra- patient |
Inter- patient |
||
| (Lower, Upper) | ||||||||
| Geometric LSM | N | Geometric LSM | N | CV% | CV% | |||
| Cmax (ng/mL) | 8.391 | 18 | 8.195 | 18 | 1.02 | (0.89, 1.18) | 24.6 | 45.0 |
| AUClast (ng·hr/mL) | 20.13 | 18 | 19.33 | 18 | 1.04 | (0.95, 1.14) | 16.3 | 43.0 |
| AUCinf (ng·hr/mL) | 20.86 | 18 | 19.92 | 18 | 1.05 | (0.95, 1.15) | 16.3 | 43.7 |
The parameters were natural log-transformed prior to analysis. The geometric LSM was calculated by exponentiating the LSMs from the ANOVA with treatment as a fixed effect and patient as a random effect. The estimates and CI limits of the LSM differences for the log-transformed values were exponentiated to calculate the GMR
GMR = (marker drug with TAS-115)/marker drug alone)
ANOVA analysis of variance, AUClast area under the plasma concentration-time curve up to the last observable concentration, AUCinf area under the plasma concentration-time curve from time 0 to infinity, CI confidence interval, Cmax maximum plasma concentration, CV coefficient of variation, LSM least-squares mean, GMR geometric mean ratio, PK pharmacokinetic
Effect of TAS-115 on Losartan PKs
The mean plasma concentration-time profiles of losartan following a single oral dose of 25 mg losartan with and without coadministration of 250 mg TAS-115 once daily are displayed graphically on linear and semi-log scales in Fig. 2b, respectively. After achieving peak concentrations, the mean plasma concentrations of losartan were slightly higher when it was administered with TAS-115 compared with when losartan was administered alone. Based on the statistical comparisons of natural logarithmically transformed PK parameters of losartan following coadministration with TAS-115, Cmax, AUClast, and AUCinf increased by approximately 5%, 9%, and 11%, respectively, when compared with the administration of losartan alone (Table 1b).
Effect of TAS-115 on Midazolam and 1’-Hydroxymidazolam PKs
The mean plasma concentration-time profiles of midazolam and 1’-hydroxymidazolam following a single oral dose of 2.5 mg midazolam with and without coadministration of 250 mg TAS-115 once daily are displayed graphically on linear and semi-log scales in Fig. 2c, respectively. The mean plasma concentration-time profiles of midazolam and 1’-hydroxymidazolam were similar throughout the entire sampling period when midazolam was administered with and without TAS-115. Based on the statistical comparisons of natural logarithmically transformed PK parameters of midazolam following coadministration with TAS-115, Cmax, AUClast, and AUCinf decreased by approximately 9%, 7%, and 7%, respectively, when compared with the administration of midazolam alone (Table 1, section c-1). Based on the statistical comparisons of natural logarithmically transformed PK parameters of 1’-hydroxymidazolam following coadministration with TAS-115, Cmax, AUClast, and AUCinf increased by approximately 2%, 4%, and 5%, respectively, when compared with the administration of midazolam alone (Table 1, section c-2). Comparable geometric mean metabolite-to-parent molar ratios (MRCmax, MRAUClast, and MRAUCinf) for 1’-hydroxymidazolam were observed (Data not shown).
TAS-115 PKs
The mean plasma concentration-time profiles of TAS-115 following the oral administration of 250 mg TAS-115 alone are presented in Supplementary Figure S1. The arithmetic mean (standard deviation) trough plasma concentrations following once daily TAS-115 dosing on Day 2 (24 h after Day 1 dosing), Day 4, and Day 5 were 575.8 (239.97), 834.5 (318.68), and 881.6 (378.03) ng/mL, respectively. There appeared no marked difference in mean trough concentrations between Days 4 and 5, suggesting that plasma exposure to TAS-115 had reached an approximate steady-state by Day 4.
Safety results
Safety analyses were conducted on all treated patients (n = 18) during the DDI evaluation and continuous administration periods (Table 2). Detailed adverse events related to TAS-115 are also summarized in Supplementary Tables S2-S5.
Table 2.
A brief summary of adverse events
| Drug-Drug Interaction Evaluation Period (N=18) | ||||
|---|---|---|---|---|
| Entire DDI Evaluation Period (N=18) | Before Administration of TAS-115 (N=18) | After Administration of TAS-115 (N=18) | Continuous Administration Period (N=18) | |
| N (%) | N (%) | N (%) | N (%) | |
| Any TEAEs | 15 (83.3) | 4 (22.2) | 15 (83.3) | 18 (100.0) |
| Any >=Grade 3 TEAEs | 2 (11.1) | 0 (0.0) | 2 (11.1) | 8 (44.4) |
| Any TRAEs | 15 (83.3) | 1 (5.6) | 15 (83.3) | – |
| Any >=Grade 3 TRAEs | 1 (5.6) | 0 (0.0) | 1 (5.6) | – |
| Any TRAEs Related to TAS-115 | 14 (77.8) | – | 14 (77.8) | 17 (94.4) |
| Any >=Grade 3 TRAEs Related to TAS-115 | 1 (5.6) | – | 1 (5.6) | 6 (33.3) |
| Any TRAEs Related to Pioglitazone | 1 (5.6) | 1 (5.6) | 0 (0.0) | – |
| Any >=Grade 3 TRAEs Related to Pioglitazone | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Any TRAEs Related to Losartan | 1 (5.6) | 0 (0.0) | 1 (5.6) | – |
| Any >=Grade 3 TRAEs Related to Losartan | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Any TRAEs Related to Midazolam | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Any >=Grade 3 TRAEs Related to Midazolam | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Any TEAEs Leading to Discontinuation of Study Medication | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (5.6) |
| Any TRAEs Leading to Discontinuation of Study Medication | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (5.6) |
| Any TEAEs Leading to Dose Reduction of TAS-115 | 0 (0.0) | – | 0 (0.0) | 1 (5.6) |
| Any TRAEs Related to TAS-115 Leading to Dose Reduction of TAS-115 | 0 (0.0) | – | 0 (0.0) | 1 (5.6) |
| Any TEAEs Leading to Dose Interruption of TAS-115 | 0 (0.0) | – | 0 (0.0) | 10 (55.6) |
| Any TRAEs Related to TAS-115 Leading to Dose Interruption of TAS-115 | 0 (0.0) | – | 0 (0.0) | 9 (50.0) |
| Any SAEs | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (27.8) |
| Any Treatment-Related SAEs | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (11.1) |
| Any TEAEs Leading to Death | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Any TRAEs Leading to Death | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Before Administration of TAS-115: From Day -3 to before Day 1 administration in the Drug-Drug Interaction (DDI) Evaluation Period
After Administration of TAS-115: From after Day 1 administration in DDI Evaluation Period to before the Continuous Administration Period
TEAEs treatment-emergent adverse events, TRAEs treatment-related adverse events, SAEs serious adverse events
During the DDI evaluation period, the majority of patients (83.3%) reported treatment-emergent adverse events (TEAEs). Among these, TEAEs of ≥ Grade 3 occurred in two patients [11.1%, anemia and lipase increased (one patient each)]. Treatment-related adverse events (TRAEs) were reported in 15 patients (83.3%). Of these, 14 patients experienced TRAEs related to TAS-115; one patient had a TRAE (Grade 1 hypotension) related to losartan administered after TAS-115, and one patient had a TRAE (Grade 1 diarrhoea) related to pioglitazone administered before TAS-115. Only one patient with Grade 3 or higher TRAE (anaemia) was observed, which was attributed to TAS-115. Importantly, no serious adverse events (SAEs), TEAEs leading to discontinuation, dose reduction, dose interruption, or death were reported during the DDI evaluation period.
During the continuous administration period, all patients (18/18, 100%) reported TEAEs during the continuous administration period. TEAEs occurring in ≥ 20% of patients included aspartate aminotransferase increased (55.6%), anaemia (33.3%), alanine aminotransferase increased (33.3%), blood creatine phosphokinase (CK) increased (27.8%), diarrhoea (22.2%), oedema (22.2%), platelet count decreased (22.2%), cough (22.2%), and rash (22.2%). TEAEs of ≥ Grade 3 were reported in 44.4% of patients, with notable occurrences of anaemia and gamma-glutamyltransferase increased. The majority of patients (17/18, 94.4%) experienced TRAEs related to TAS-115, with the most common including aspartate aminotransferase increased (55.6%), alanine aminotransferase increased (33.3%), anemia (27.8%), blood CK increased (27.8%), platelet count decreased (22.2%), and rash (22.2%). TRAEs of ≥ Grade 3 related to TAS-115 were reported in 33.3% of patients, with anaemia occurring in 11.1%. No criteria for severe drug-induced liver injury (Hy’s law) were met. No deaths occurred during the continuous administration period or within 30 days following discontinuation of TAS-115. Five patients (27.8%) experienced SAEs including cardiac tamponade, ileus, vomiting, tumor haemorrhage, and rash maculo-papular. Vomiting and rash maculo-papular were related to TAS-115. All events were resolved or were resolving at the end of the observation period, except for cardiac tamponade. One patient experienced a Grade 3 rash maculo-papular, leading to discontinuation of TAS-115. The patient recovered after discontinuation. Ten patients (55.6%) required dose interruption by AEs. One patient (5.6%) required dose reduction due to AEs related to TAS-115.
Overall, TAS-115 was associated with manageable AEs, with no major safety concerns identified.
Efficacy results
The efficacy results in the continuous administration period are presented in Table 3; Fig. 3. Sixteen patients were evaluable for drug efficacy. The ORR was 6.3% (95% CI: 0.2%–30.2%), and the DCR was 37.5% (95% CI: 15.2%–64.6%). The median PFS was 2.1 months (95% CI: 1.6–4.0). A subpopulation of four patients with osteosarcoma exhibited a tendency towards greater efficacy, although data are limited. The ORR was 25.0% (95% CI: 0.6%–80.6%) and the DCR was 50.0% (95% CI: 6.8%–93.2%). The median PFS was 7.0 months (95% CI: 3.2– not estimable). The median OS was 13.8 months (95% CI: 11.1– not estimable). Longer treatment periods were observed compared with the overall patient population. One patient with osteosarcoma in the target region (in both left and right lungs) had the longest treatment period (27 months) and the ORR was SD (Supplementary Figure S2). No explicit changes in bone metabolism markers were observed among four patients with osteosarcoma.
Table 3.
Brief summary of efficacy results
| Efficacy-evaluable population | ||
|---|---|---|
| All patients (N=16) | Osteosarcoma (N=4) | |
| Efficacy | N (%) | |
| CR | 0 (0.0) | 0 (0.0) |
| PR | 1 (6.3) | 1 (25.0) |
| SD | 5 (31.3) | 1 (25.0) |
| PD | 10 (62.5) | 2 (50.0) |
| Response rate (CR+PR) | 1 (6.3) | 1 (25.0) |
| 95%CI (%) | [0.2, 30.2] | [0.6, 80.6] |
| Disease control rate (CR+PR+SD) | 6 (37.5) | 2 (50.0) |
| 95%CI (%) | [15.2, 64.6] | [6.8, 93.2] |
| Progression-free survival | N (%) | |
| Event | 14 (87.5) | 4 (100.0) |
| Censored | 2 (12.5) | 0 (0.0) |
| Median (month) | 2.1 | 7.0 |
| 95%CI (month) | [1.6, 4.0] | [3.2, -] |
| Overall survival | N (%) | |
| Event | 3 (75.0) | |
| Censored | 1 (25.0) | |
| Median (month) | 13.8 | |
| 95%CI (month) | [11.1, -] | |
CR complete response, PR partial response, SD stable disease, PD progressive disease, CI confidence interval
Fig. 3.
The tumor reduction rate in a Waterfall plot. *Osteosarcoma
Discussion
The primary objective of this study was to evaluate the PK effects of TAS-115 on pioglitazone (a CYP2C8 substrate), losartan (a CYP2C9 substrate), and midazolam (a CYP3A substrate) in patients with solid tumors. All 18 enrolled patients were included in the analysis populations. The administration of a daily dose of 250 mg TAS-115 demonstrated minimal to no impact on the systemic exposure of these substrates. Specifically, the Cmax of pioglitazone showed a slight increase when coadministered with TAS-115, with a GMR of 1.24 (90% CI: 1.05–1.47). Although the upper 90% CI exceeded the default no-effect boundary of 0.8 to 1.25 (guideline on drug interaction for drug development and appropriate provision of information) [20], the point estimate increase in Cmax was modest (24%). The observed 24% increase in Cmax is not considered clinically relevant for pioglitazone, as no TRAEs associated with pioglitazone were observed during combination with TAS-115. The increases in AUClast and AUCinf for pioglitazone were negligible (8% and 1%, respectively), and their 90% CIs were within the no-effect boundary. This suggests that clinically relevant PK interactions between TAS-115 and CYP2C8 substrates are unlikely. For losartan, coadministration with TAS-115 resulted in marginal increases in Cmax, AUClast, and AUCinf (5%, 9%, and 11%, respectively). However, the upper limits of their 90% CIs (1.38, 1.28, and 1.26, respectively) exceeded the 1.25 boundary. Despite this, the point estimates were well below the 1.25 threshold for weak inhibitors [20], indicating an insignificant interaction between TAS-115 and CYP2C9 substrates. Midazolam coadministration with TAS-115 exhibited no impact on its PKs, as the 90% CI for GMR of Cmax, AUClast, and AUCinf were all within the no-effect boundary (0.8 to 1.25). Further, the metabolite-to-parent molar ratios for 1’-hydroxymidazolam were consistent, suggesting no effect on CYP3A-mediated metabolism.
Time-dependent inhibitors, like TAS-115, typically require a longer duration of administration to achieve their maximal DDI effect, even if plasma exposure has attained steady state. In the present study, considering the recovery of CYP3A activity during a 2-day off following consecutive 5-day dosing of TAS-115, midazolam was administered after the 5 days of TAS-115 administration (i.e., Day 5). To ensure the appropriateness of the study design for evaluating the maximum DDI impact of TAS-115, a preliminary physiologically-based PK model for TAS-115 was used to simulate the time profile of CYP3A activity prior to the study. Based on the simulation (data on file), inhibition of CYP3A activity in the gut and liver would reach a maximum after 5 days of administration, and there would be little additional inhibitory effect after a 2-day off and a further 5 days of dosing (i.e., Day 12). Therefore, it is likely that the negligible effect of TAS-115 on midazolam PK observed after 5 days reflects the maximal inhibitory effect, supporting the appropriateness of our study design.
Regarding safety in the DDI evaluation period, only two TEAEs of Grade ≥ 3 were recorded, comprising anemia and increased lipase (one patient each). Only the anemia was potentially related to TAS-115 use. There were no deaths, SAEs, or AEs leading to discontinuation, dose reduction, or interruption of the study medication. This indicates that TAS-115 in combination with the studied substrates is well-tolerated in patients with solid tumors.
Given the minimal impact of TAS-115 on the PK of the CYP substrates tested in this study and the absence of significant safety concerns, TAS-115 may be incorporated into therapeutic regimens containing these CYP substrates, following regulatory approval. Extensive PK monitoring for these specific DDIs is not considered necessary. Future research could expand on these findings by exploring interactions with a broader range of CYP substrates and including larger, more diverse patient populations. Additionally, future studies should investigate the long-term safety and efficacy of TAS-115 in combination with other therapies.
In conclusion, our findings showed that TAS-115 had a limited impact on DDI mediated by CYP3A4, CYP2C9, and CYP2C8 and was well-tolerated in patients with solid tumors. Further, the antitumor efficacy and safety profile of TAS-115 suggest its potential as a treatment option for osteosarcoma, despite the limited number of patients evaluated here. This study provides evidence that the efficacy and safety of TAS-115 can be maximized even when used in combination with drugs metabolized via these CYP enzymes. Additionally, our overall evaluation method, that includes a continuous administration period after the DDI evaluation period and which allows patient participation if they wish, offers a valuable example of a clinical protocol. This protocol minimizes patient burden while ensuring potential clinical benefits and safety.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the patients who participated in this trial and their families, all the investigators, and the members of the Data Monitoring Committee, as well as the coordinators and study site personnel. This study was supported by Taiho Pharmaceutical Co, Ltd. The sponsor was involved in the design and conduct of the study, analysis of data, and approval of the manuscript. No grant numbers are applicable.
Author contributions
All the authors: Investigation, Resources, Writing—Review & Editing. Yuki Katsuya: Writing—Original Draft, Visualization, Supervision. Satoshi Takenaka: Supervision. Shunji Takahashi: Supervision. Noboru Yamamoto: Conceptualization, Methodology, Supervision. The author(s) read and approved the final manuscript.
Funding
This work was supported by Taiho Pharmaceutical Co., Ltd. The company participated in study design and analysis and the interpretation of data.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
N Yamamoto has received research grants as principal investigator (in institutional capacity) from Astellas Pharma, Chugai, Eisai, Taiho Pharmaceutical, Bristol-Myers Squibb, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono Pharmaceutical, Janssen Pharma, MSD, MERCK, GSK, Chiome Bioscience, Otsuka Pharmaceutical, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, InventisBio, Rakuten Medical, Amgen, Bicycle Therapeutics, and Zymeworks. N Yamamoto has received consulting fees (in personal capacity) from Eisai, Boehringer Ingelheim, Cmic, Chugai, MERCK, Healios, Mitsubishi Tanabe, Rakuten Medical, IQVIA, Noile-Immune Biotech, and Janssen Pharma. N Yamamoto has received payments for lectures (in personal capacity) from Chugai, Daiichi-Sankyo, and Eisai. Y Katsuya has received support for traveling to meetings not for the current study, but for another study from Ono Pharmaceutical. S Takenaka and S Takahashi declare that they have no conflicts of interest.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.