Dataset Information

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

ABSTRACT: PURPOSE: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). METHODS: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. RESULTS: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. CONCLUSIONS:Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. TRIAL REGISTRATION:ClinicalTrials.gov NCT00702182.

SUBMITTER: Sutiman N

PROVIDER: S-EPMC4852941 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Sutiman Natalia N Zhang Zhenxian Z Tan Eng Huat EH Ang Mei Kim MK Tan Shao-Weng Daniel SW Toh Chee Keong CK Ng Quan Sing QS Chowbay Balram B Lim Wan-Teck WT

PloS one 20160502 5

<h4>Purpose</h4>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).<h4>Methods</h4>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 wit ...[more]

PMID: 27135612

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Project description:Micro-abstractIn a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage.IntroductionWe present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability.ResultsTwenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect.ConclusionDaily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.

Dataset Information

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

Publications

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

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