First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity
| Autor: | Michael Millward, Chuan Qi, Jian Wang, Jason D. Lickliter, Weiguo Su, Ye Hua, Lilin Zhang, Liu Yang, Yang Sai, Hui K Gan, Shethah Morgan, Melanie M. Frigault |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research medicine.medical_specialty Cabozantinib Peripheral edema Cmax Gastroenterology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Neoplasms Internal medicine Biomarkers Tumor medicine Humans Molecular Targeted Therapy Neoplasm Metastasis Adverse effect Protein Kinase Inhibitors Neoplasm Staging Triazines Sunitinib business.industry Proto-Oncogene Proteins c-met Treatment Outcome 030104 developmental biology Oncology chemistry Tolerability Savolitinib Pyrazines 030220 oncology & carcinogenesis Female Drug Monitoring Neoplasm Grading medicine.symptom business medicine.drug |
| Zdroj: | Clinical Cancer Research. 25:4924-4932 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib). Patients and Methods: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity. Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg N = 1, 800 mg N = 1, and 1,000 mg N = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, Cmax was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks. Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC. |
| Databáze: | OpenAIRE |
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