Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

• Published in: PloS one Vol. 11; no. 5; p. e0154316
• Main Authors: Sutiman, Natalia, Zhang, Zhenxian, Tan, Eng Huat, Ang, Mei Kim, Tan, Shao-Weng Daniel, Toh, Chee Keong, Ng, Quan Sing, Chowbay, Balram, Lim, Wan-Teck
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.05.2016; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Analysis; Antineoplastic Combined Chemotherapy Protocols; Biology and Life Sciences; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Chemotherapy; Combination drug therapy; Dosage and administration; Drug Administration Schedule; Drug dosages; Drug therapy; Epidermal growth factor; Erlotinib; Erlotinib Hydrochloride - administration & dosage; Erlotinib Hydrochloride - pharmacokinetics; Erlotinib Hydrochloride - therapeutic use; Female; Health services; Humans; Hyponatremia; Inhibitor drugs; Lung cancer; Lung diseases; Male; Medicine and Health Sciences; Middle Aged; Mutation; Neutropenia; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Patients; Pharmacokinetics; Pharmacology; Quality; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Quinazolines - therapeutic use; Research and Analysis Methods; Safety and security measures; Safety engineering; Schedules; Steady state; Toxicity; Treatment Outcome; Tumors; Vinblastine - administration & dosage; Vinblastine - analogs & derivatives; Vinblastine - pharmacokinetics; Vinblastine - therapeutic use; Vinorelbine; Japan; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154316

This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. ClinicalTrials.gov NCT00702182.