lenvatinib and Nausea

This 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.. Patients 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 %.. 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.. The 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.

Topics: Adult; Area Under Curve; Asian People; Female; Headache; Humans; Japan; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; Thrombocytopenia; Treatment Outcome

E7080, an oral multitargeted receptor tyrosine kinase inhibitor, has antiangiogenic and antitumor activity. This Phase I study investigated maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in patients with advanced solid tumors.. In this sequential, dose-escalation, open-label study E7080 was administered orally twice daily in a 2-week-on/1-week-off cycle. Plasma angiogenic proteins, circulating endothelial cells (CEC) and circulating progenitor cells (CEP) were measured for biomarker analysis.. Twenty-seven patients (median age 53 years, performance status 0/1) were enrolled. E7080 was escalated from 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg bid by conventional 3-patient cohorts. During cycle 1, no grade 3/4 toxicity was observed up to 13 mg bid. DLTs included grade 3 AST/ALT increase in 1 patient at 16 mg bid and grade 3 platelet count decrease in 2 patients at 20 mg bid. The MTD of 13 mg bid was determined. After repeated doses, C(max) and area under the plasma concentration-time curve increased in a dose-dependent manner. After 14 days' treatment, c-kit(+) CEPs and CECs significantly decreased in cycle 1, but c-kit(-) CEPs and CECs did not. Change from baseline in c-kit(+) CEC ratio in cycle 1 and baseline SDF1α, c-kit(+) CEPs and c-kit(+) CEP ratio significantly correlated with the E7080 therapeutic effect.. E7080 has manageable toxicity up to 13 mg bid when administered in a 2-week-on/1-week-off cycle and shows preliminary activity for durable disease control. Biomarker analysis suggested antiangiogenic activity correlated with antitumor activity in patients with a wide range of solid tumors.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Biomarkers, Tumor; Chemokine CXCL12; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelial Cells; Fatigue; Female; Headache; Humans; Hypertension; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Quinolines; Stem Cells; Treatment Outcome

Glioblastoma is the most aggressive primary brain tumor that originates from the glial cells in adults. Aberrant angiogenesis is essential for malignant glioblastoma tumorigenesis, development and metastasis. Lenvatinib is a multi‑targeted anticancer agent that targets of receptor tyrosine kinases including vascular endothelial growth factor receptor 1 and 2, fibroblast growth factor receptor 1, platelet‑derived growth factor receptor β and v‑kit Hardy‑Zuckerman 4 feline sarcoma viral oncogene homolog. In the present study, the therapeutic effects of lenvatinib as a treatment for glioblastoma were investigated in vivo and in vitro. The maximum dose toxicity (MDT) and treatment‑associated adverse events of lenvatinib were identified by cytotoxicity assay in experimental mice. Increasing levels of the pro‑apoptosis genes caspase‑3, -8, -9 and -10 following lenvatinib treatment were determined by reverse transcription‑quantitative polymerase chain reaction, and apoptosis of the malignant gliomas cells was analyzed by FACS. In vivo treatment with lenvatinib for BV‑2 bearing male BALC/c nude mice was assessed via tumor growth suppression and long‑term observation of survival. Subsequent cytotoxic T lymphocyte responses were further analyzed to determine the in vivo efficacy of lenvatinib treatment in mice with glioblastoma. The MDT of lenvatinib was identified as 0.24 mg, with relatively few side effects and improved efficacy in mice. Lenvatinib (0.24 mg) significantly increased apoptosis in BV‑2, C6, BC3H1 and G422 glioma cell lines. Tumor growth was significantly inhibited and tumor‑bearing mice demonstrated an improved survival rate following treatment with lenvatinib. In conclusion, lenvatinib provided an effective treatment outcome, and the results of the present study may help to achieve a comprehensive therapeutic schedule for clinical application.

Topics: Animals; Apoptosis; Brain Neoplasms; Caspases; Cell Line, Tumor; Glioblastoma; Humans; Hypertension; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nausea; Neoplasm Staging; Phenylurea Compounds; Protein Kinase Inhibitors; Quinolines; RNA, Messenger; T-Lymphocytes, Cytotoxic; Transplantation, Heterologous