First-in-human study of E7130 (a tumor microenvironment-ameliorating microtubule inhibitor) in patients with advanced solid tumors: Primary results of the dose-escalation part.

BACKGROUND: E7130 is a novel anticancer agent created from a total synthetic study of norhalichondrin B. The authors report the E7130 dose-escalation part of a first-in-human study of patients with advanced solid tumors (NCT03444701). METHODS: Japanese patients ≥20 years of age were enrolled. E7130 was administered intravenously in two cycles: day 1 of a 21-day cycle (Q3W) or days 1 and 15 of a 28-day cycle (Q2W). Doses were escalated from 270 to 550 µg/m2 for the Q3W group or 25-400 µg/m2 for the Q2W group. The primary end point of the dose-escalation phase was safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs) and adverse events. Other end points included determination of the maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics. RESULTS: Forty-four patients were enrolled: 15 in the E7130 Q3W group and 29 in the Q2W group. Treatment-emergent adverse events (TEAEs) occurred in all patients; the most common TEAE overall was leukopenia (78.6%). Grade 3-4 TEAEs occurred in 93.3% of patients in the Q3W group and 86.2% of patients in the Q2W group. None had a TEAE resulting in study drug discontinuation, and no treatment-related deaths were reported. Per the DLT evaluation, the MTDs were determined as 480 µg/m2 Q3W and 300 µg/m2 Q2W. Significant changes in multiple plasma biomarkers, including vascular endothelial growth factor 3 and matrix metallopeptidase 9, were dose-dependent after initial doses of 350-480 µg/m2 . CONCLUSIONS: E7130 480 µg/m2 Q3W was chosen for the dose-expansion part over 300 µg/m2 Q2W primarily per dose-dependent biomarker results.

A phase I pharmacokinetic study of lenvatinib in Chinese patients with unresectable hepatocellular carcinoma.

Aim: This phase I study assessed the pharmacokinetic profile, safety and antitumor activity of lenvatinib in Chinese patients with unresectable hepatocellular carcinoma. Materials & methods: Bodyweight-based lenvatinib dosing was administered (patients <60 kg: 8 mg/day, n = 13; patients ≥60 kg: 12 mg/day, n = 12). Pharmacokinetic sampling was performed during the first cycle. Efficacy and safety were assessed. Results: There was considerable overlap between individual exposure values at steady-state in the 8 and 12 mg groups. The most common adverse events were increased blood bilirubin and decreased platelet count (48.0%). Two patients had partial responses, and 16 patients attained stable disease. Conclusion: No significant pharmacokinetic differences between dose groups were detected. Lenvatinib was tolerable, showing promising antitumor activities in Chinese patients with unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC; liver cancer) is common in Chinese patients. Lenvatinib is a drug approved to treat HCC, and patients with higher bodyweights are given a higher dose than patients with lower bodyweights. This trial in Chinese patients with HCC looked at lenvatinib pharmacokinetics (what the body does to a drug) after one dose and multiple doses, and at lenvatinib's antitumor activity and side effects. Meaningful differences in pharmacokinetics between the higher and lower doses after a single dose or multiple doses of daily lenvatinib were not observed. Lenvatinib partially shrank the tumors of 2 out of 21 patients whose tumors were assessed. The side effects seen matched those from other studies of lenvatinib in HCC and other cancers. ClinicalTrial Registration: NCT02953743 (ClinicalTrials.gov).

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma.

BACKGROUND: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. METHODS: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. RESULTS: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. CONCLUSIONS: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.

Pharmacokinetic study of lenvatinib in Chinese patients with solid tumors.

Aim: To assess the pharmacokinetics of once-daily oral lenvatinib 24 mg in Chinese patients. Material & methods: Patients had any solid tumor (except hepatocellular carcinoma) that was resistant to standard antitumor therapies or for which no appropriate treatment was available. Results: Twelve patients were enrolled. Maximum plasma concentrations of lenvatinib were observed at 2 and 4 h (median) after single and multiple doses (day 15), respectively. Steady state was achieved within 8 days. The geometric mean maximum observed concentration at steady state was 258 ng/ml (coefficient of variance: 49.2%); and the geometric mean area under the concentration-time curve from zero to 24 h at steady state was 3090 ng•h/ml (coefficient of variance: 44.7%). No accumulation was seen after 15 days. Conclusion: Lenvatinib pharmacokinetic data in Chinese patients are consistent with data in multinational trials, supporting usage of the 24-mg dose. Clinical trial registration: NCT03009292 (ClinicalTrials.gov).

Bioequivalence of perampanel fine granules and tablets in healthy Japanese subjects.

OBJECTIVE: Perampanel is an approved anti-seizure drug. A new formulation of perampanel fine granules (FG; 1% perampanel) has been developed for patients who are unable to take tablets. Bioequivalence between the 4-mg FG and tablet perampanel formulations, as well as their safety and tolerability, were assessed. MATERIALS AND METHODS: In this phase I, single-center, open-label, 2-period, 2-sequence, crossover, bioequivalence study (NCT03399734), healthy Japanese subjects were randomized to receive single doses of the 4-mg FG perampanel and 4-mg perampanel tablet (separated by a ≥ 6-week washout period). Plasma samples for perampanel concentration analysis were collected pre-dose and at intervals up to 168 hours post-dose. The maximum observed concentration (Cmax) and area under the concentration-time curve from time zero to 168 hours (AUC(0-168h)) were used to assess the bioequivalence of the two formulations. RESULTS: The 90% confidence intervals (CIs) for the geometric mean ratio of test/reference for Cmax and AUC(0-168h) were within the bioequivalence criteria of 80 - 125% (Cmax 90% CI 90.8%, 110%; AUC(0-168h) 90% CI 98.2%, 112%; N = 21). 10/24 (41.7%) subjects with FG experienced ≥ 1 treatment-emergent adverse event (TEAE). The events were mild in severity and resolved within 4 hours of onset. There were no deaths, severe TEAEs, serious AEs, or TEAEs leading to study-drug withdrawal. CONCLUSION: Bioequivalence of 4-mg FG and 4-mg tablet of perampanel was demonstrated. Both perampanel formulations were generally safe and well tolerated. These data suggest that perampanel FG may be a suitable alternative formulation for patients with epilepsy who have difficulties taking perampanel tablets.

A Single- and Multiple-Dose Pharmacokinetic Study of Oral Perampanel in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: Perampanel is a once-daily oral anti-seizure medication indicated for focal-onset seizures and generalized tonic-clonic seizures. This study investigated the single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults. METHODS: Study 052 (NCT03424564) was a phase I, single-center, open-label, parallel-group study. In the single-dose part of the study, subjects received a single oral dose of perampanel 2, 4, or 8 mg. In the multiple-dose part, subjects received once-daily oral perampanel 2 mg on Days 1-7 and 4 mg on Days 8-21. Pharmacokinetic parameters were determined from perampanel plasma concentrations using non-compartmental analysis. Dose proportionality after single doses of perampanel was assessed. Safety and tolerability were evaluated. RESULTS: In the single-dose part (N = 30), median time to reach maximum concentration (tmax) was 0.75-1.0 h, mean terminal elimination phase half-life (t½) was 85.6-122 h, mean maximum observed concentration (Cmax) was 77.9-276 ng/mL, and mean area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) was 4070-15100 ng·h/mL. Single-dose pharmacokinetics were linear for perampanel 2-8 mg. In the multiple-dose part (N = 12), Day 21 steady-state (4 mg/day) parameters were median time at which the highest drug concentration occurs at steady state (tss,max), 1.25 h; mean t½, 109 h; mean maximum observed concentration at steady state (Css,max), 453 ng/mL; and mean area under the concentration-time curve over the dosing interval on multiple dosing (AUC(0- τ)), 7540 ng·h/mL. For single- and multiple-dose perampanel, the most common treatment-emergent adverse events were dizziness and somnolence. CONCLUSIONS: Single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults revealed rapid perampanel absorption, slow elimination, and a linear relationship with single perampanel doses of 2-8 mg. Findings were consistent with previous studies of perampanel pharmacokinetics in other ethnic/racial populations of healthy subjects. Single and multiple doses of perampanel were generally safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT03424564; registered February 2018.

Pharmacokinetics of Perampanel in Healthy Korean, White, and Japanese Adult Subjects.

Perampanel is a highly selective, orally active, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that has been approved in many countries as a treatment for partial-onset seizures and primary generalized tonic-clonic seizures. The pharmacokinetics (PK) of perampanel following multiple doses in healthy Korean, white, and Japanese male subjects were assessed in 3 studies. Noncompartmental PK parameters were derived from plasma concentration-time data. At steady state of perampanel 2-, 4-, and 6-mg oral multiple administration, perampanel was rapidly absorbed, as plasma perampanel concentration reached maximum concentration after 0.55-1 hour (median) after dosing in all 3 ethnic groups. The elimination was slow, with terminal elimination phase half-life values ranging from 63.9-129 hours (mean) for doses of 2-6 mg; there was no specific tendency suggesting a dose-related effect, and perampanel PK were linear in Korean subjects. There were no clinically relevant ethnic differences in PK following multiple doses of perampanel 2 and 4 mg between Korean, white, or Japanese subjects. Perampanel was well tolerated by all 3 ethnic groups. This outcome indicates that with respect to PK, the dosing regimens established in white and Japanese patients are applicable to Korean patients.