A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors

Abstract

PurposeThis phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24 mg on a once-daily (QD) continuous schedule.MethodsPatients were enrolled in one of the two sequential cohorts (20 or 24 mg) of lenvatinib on a 28-day cycle based on the conventional 3 + 3 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33 %.Results Nine patients received lenvatinib [20 mg (n = 3); 24 mg (n = 6)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89 %), followed by leukopenia, headache, and proteinuria (78 %). The area under the concentration–time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6 months.ConclusionsThe 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.

Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study

“…A high incidence of PPES in Japanese patients was also observed in several studies of lenvatinib monotherapy . Hematological toxicities were observed in Japanese patients treated with lenvatinib or everolimus monotherapy . ILD was observed in three patients with interruption of the combination therapy in the present study.…”

“…However, Japanese patients who received the combination therapy had relatively high incidences of PPES and hematological toxicities, such as thrombocytopenia and lymphopenia. A high incidence of PPES in Japanese patients was also observed in several studies of lenvatinib monotherapy . Hematological toxicities were observed in Japanese patients treated with lenvatinib or everolimus monotherapy .…”

“… †Data from a non‐Japanese phase 2 study . ‡Data from Japanese phase 1 studies . §AUC (0− t ) (the concentrations at 24 h after administration [nominal time] in all patients were quantifiable).…”

Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis

“…The dose of lenvatinib administered in patients with solid tumors varied in different situations, but in 8 [15, 16, 18–20, 22, 23, 26] of the 14 included studies, patients received lenvatinib at a daily dose of 24 mg per day in 28-day cycles, and two studies [18, 20] demonstrated that the 24-mg QD dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in patients with solid tumors.…”

Successful recovery from a subclavicular ulcer caused by lenvatinib for thyroid cancer: a case report

“…It was a problem as to how long lenvatinib should be withdrawn before and after surgery in this case. The half-life of lenvatinib is about 30 h [12, 13]. The drug is pharmacologically metabolized during a period of approximately five times the half-life.…”