A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors

This study enrolled adult patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors for whom no effective standard treatment was available. Patients were required to have: an Eastern Cooperative Oncology Group performance status of 0 or 1; a left ventricular ejection fraction ≥ 50%, as measured by echocardiogram or multiple gated acquisition scan; and adequate bone marrow reserve, and renal and hepatic function (absolute neutrophil count ≥ 1.5 × 10⁹/L; platelet count ≥ 75 × 10⁹/L; hemoglobin ≥ 85 g/L; bilirubin ≤ 1.5 × upper limit of normal [ULN]; alanine transaminase or aspartate transaminases ≤ 3.0 × ULN [elevation of either up to 5 × ULN was permitted if ascribed to underlying liver metastases]; and serum creatinine < 1.5 × the institutional ULN or estimated [Cockcroft-Gault formula] creatinine clearance of ≥ 30 mL/min for patients with serum creatinine concentrations above institutional limits). Patients were excluded: if they had received treatment with systemic anticancer treatments or investigational products within 28 days before the first TAK-931 dose or 5 half-lives, whichever was shorter; if they required continuous use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists, or had received treatment with PPIs within 5 days before the first dose of study drug; if they had received treatment with clinically significant enzyme inducers, such as phenytoin, carbamazepine, enzalutamide, mitotane, ritonavir, rifampin, or St John's wort within 14 days before the first TAK-931 dose; had hypertension that was not controlled with standard treatment; or had a known gastrointestinal disease or procedure that could interfere with the absorption of TAK-931. Patients with brain metastases were eligible if there was no evidence of progression for at least 4 weeks after central nervous system-directed treatment, assessed by clinical examination and brain imaging (magnetic resonance imaging or computed tomography) during screening. Patients had to have a radiographically or clinically evaluable tumor, but measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was not required. Full inclusion and exclusion criteria are described in the Supplementary Materials.

The study was conducted in accordance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, in accordance with the International Conference on Harmonisation Good Clinical Practice standards and applicable regulatory requirements, and in compliance with the Institutional Review Board regulations stated in the Good Clinical Practice regulations and guidelines. All patients provided written informed consent. The trial was designed in accordance with US Food and Drug Administration (FDA) guidelines on bioavailability and bioequivalence studies [13], and is registered at ClinicalTrials.gov (NCT03708211).

The relative bioavailability of the tablet in reference to the PIC formulation was characterized in a crossover PK study design (Supplementary Fig. 1). Patients were randomized 1:1 to receive one dose of TAK-931 80 mg PIC on Day 1 of Cycle 0 followed by one dose of TAK-931 80 mg tablet on Day 3, or to receive the reverse sequence. TAK-931 was administered on an empty stomach, except for water, from 2 h before taking the study drug until completion of collection of the 4-h ECG/PK samples on Day 1 and Day 3 of Cycle 0. Blood samples were collected predose and up to 48 h postdose at predetermined time points to measure plasma drug concentrations In both schedules, TAK-931 50 mg PIC was then administered once daily (QD) for 12 days starting from Day 5, followed by a 7-day rest period in Cycle 0. From Cycle 1, all patients received 50 mg PIC QD on Days 1–14 followed by a 7-day rest period in 21-day treatment cycles. Patients continued treatment for 1 year or until they experienced disease progression, unacceptable toxicity, or any other discontinuation criteria were met.

The primary endpoints were the ratio of geometric means of the following PK parameters for TAK-931 tablets in reference to PIC and associated 2-sided 90% confidence intervals (CIs): maximum observed plasma concentration (C_max), area under the plasma concentration–time curve (AUC) from time 0 to time of the last quantifiable concentration (AUC_last), and the AUC from time 0 to infinity (AUC_inf). Secondary endpoints were PK parameters of TAK-931 80 mg following a single-dose administration as PIC or tablet (time of first occurrence of maximum observed plasma concentration [T_max], and terminal disposition phase half-life [T_1/2z]), antitumor activity, and safety.

Blood samples for PK analysis were collected within 1 h before dosing and at 30 min, and 1, 2, 4, 6, 8, 24, and 48 h post-dose in Cycle 0, Days 1 and 3. Plasma concentrations of TAK-931 were determined using a validated liquid chromatography tandem mass spectrometry method [14], with a dynamic range of 0.5 to 500 ng/mL. Toxicity was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and disease response was assessed by the investigator according to RECIST version 1.1.

Relative bioavailability analysis of the tablet formulation relative to the PIC formulation was performed by an analysis of variance on C_max and AUC_0-last/AUC_0-inf. The relative bioavailability of the tablet versus PIC formulation was estimated as the ratio of geometric mean values of C_max and AUC_0–last/AUC_0-inf, (tablet:PIC), and associated 2-sided 90% CI. TAK-931 PK parameters were estimated using noncompartmental methods with WinNonlin Phoenix version 6.2 (Pharsight Corporation, Mountain View, CA, USA). Descriptive statistics for TAK-931 plasma concentrations and PK parameters are reported by formulation.

It was calculated that approximately 14–16 PK-evaluable patients were required; the sample size calculation was based on the expected 2-sided 90% CI for the difference in the paired, log-transformed AUC (or C_max) means on Days 1 and 3. According to preliminary data obtained from study NCT02699749, the within-patient coefficient of variation was estimated to be 35.0% for AUC and 36.9% for C_max, respectively. Assuming the AUC ratio of the two formulations (tablet vs PIC) was 1, with a sample size of 14, the 90% CI for the AUC ratio was expected to be (0.795–1.257) for AUC and (0.786–1.272) for C_max. Patients who were not PK-evaluable may have been replaced to ensure the availability of 14–16 PK-evaluable patients in the final analysis. Assuming that up to 4–6 patients would need to be replaced, approximately 20 patients were planned for enrollment.

A total of 20 patients were randomized to receive TAK-931; of these, 8 received the tablet formulation first and 12 received the PIC formulation first in Cycle 0. All patients discontinued treatment: 16 due to progressive disease (PD), 2 due to symptomatic deterioration, and 2 for unspecified reasons. Baseline demographics and disease characteristics are described in Table 1. Overall, median age was 63 years (range 43–84) and 12 (60%) patients were male. The most common diagnoses were colon cancer (n = 5), and non–small cell lung cancer and rectal cancer (n = 2 each); all other cancer types occurred in 1 patient each. All patients had received prior therapy, with 8 (40%) patients receiving ≥ 4 previous lines of therapy.

All patients (N = 20) were included in the assessment of relative bioavailability of TAK-931 tablet in reference to PIC. Mean TAK-931 plasma concentration–time profiles following single-dose oral administration at 80 mg as tablet or PIC are shown in Fig. 1. A summary of key PK parameters is shown in Table 2. Following single oral-dose administration of TAK-931 at 80 mg, median T_max was achieved approximately 2 h post-dose for both tablet and PIC. The geometric mean C_max and AUC exposures of TAK-931 were similar following administration as tablet and PIC. T_1/2z was also similar (7.5 h) following oral dosing as tablet or PIC. Inter-patient variability in systemic exposure (coefficient of variation) was comparable with tablet and PIC formulations. Individual comparisons of C_max and AUC_inf following administration as tablet or PIC are shown in Supplementary Fig. 2.

The statistical analyses of TAK-931 exposures for the estimation of relative bioavailability of TAK-931 as tablet in reference to PIC are shown in Table 2. Geometric mean C_max and AUC exposures of TAK-931 were similar following administration as tablet or PIC. The geometric mean C_max ratio was 0.936 with an associated 90% CI of (0.808–1.084) for TAK-931 tablet in reference to PIC. The geometric mean AUC_last ratio was approximately 1 with a 90% CI of (0.899–1.120) for TAK-931 tablet versus PIC. The geometric mean AUC_inf ratio was approximately 1 with a 90% CI of (0.903–1.123) for TAK-931 tablet in reference to PIC.

All patients received at least one dose of study drug and were included in the safety analysis, summarized in Table 3. Most patients completed at least three treatment cycles, with a median number of doses of 42 and a median dose intensity of 100%. Overall, 10 (50%) patients had at least one dose modification, including 3 (15%) patients whose dose was reduced. The most common reason for dose modification, in 7 (35%) patients, was treatment-emergent adverse events (TEAEs). A total of 19 (95%) patients experienced at least one TEAE; the most common included fatigue, (65%), constipation, (40%), nausea (40%), vomiting (30%), and alopecia (30%) (Table 4). Overall, 8 (40%) patients experienced at least one grade ≥ 3 TEAE; the most common were neutropenia and ileus (each reported in 10% of patients). One patient with rectal cancer died due to PD; this was not considered related to treatment with TAK-931. Seventeen (85%) patients experienced at least one treatment-related TEAE, the most common being fatigue (50%), alopecia (30%), nausea (30%), and vomiting and decreased appetite (both 20%). Two (10%) patients reported at least one grade ≥ 3 treatment-related TEAE; 1 patient with neutropenia, and the other with neutropenia and hypertension. One patient experienced three TEAEs (aphasia, headache, and disturbance in attention) resulting in TAK-931 discontinuation. Four (20%) patients experienced a serious TEAE, but none of the reported events were considered related to TAK-931.

A total of 19 patients were evaluable for response. No partial or complete responses to TAK-931 were seen. Four (21%) patients had a best response of stable disease (SD), with individual progression-free survival durations of 3.58, 2.23 + (censored observation), 3.55, and 4.01 months. Median time to PD or death was 1.9 months (95% CI: 1.6–2.8).