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Clinical Trial
. 2016 May 2;11(5):e0154316.
doi: 10.1371/journal.pone.0154316. eCollection 2016.

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

Natalia Sutiman  1 , Zhenxian Zhang  1 , Eng Huat Tan  2 , Mei Kim Ang  2 , Shao-Weng Daniel Tan  2 , Chee Keong Toh  2 , Quan Sing Ng  2 , Balram Chowbay  1   3   4 , Wan-Teck Lim  2   4   5
Affiliations
Clinical Trial

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

Natalia Sutiman et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: NS, ZZ and BC are employed by Singapore Health Services Pte Ltd. This does not affect the authors' adherence to PLOS policies on data and materials sharing. Authors TEH, AMK, DTSW, TCK, NQS and WTL have no competing interests to declare.

Figures

Fig 1
Fig 1. CONSORT Flow diagram.
Fig 2
Fig 2
Mean plasma concentration-time curves of vinorelbine (A) on Day 1 after initial oral dose with CSV schedule, (B) on Day 10 at steady state after oral dose with CSV schedule, (C) on Day 1 after initial oral dose with MSV schedule, and (D) on Day 10 at the steady state after oral dose with MSV schedule.
Fig 3
Fig 3
Mean plasma concentration-time curves of erlotinib (A) on Day 3 after initial oral dose with CSV dosing regimen of vinorelbine, (B) on Day 10 at the steady state after oral dose with CSV dosing regimen of vinorelbine, (C) on Day 3 after initial oral dose with MSV dosing regimen of vinorelbine and (D) on Day 10 at the steady state after oral dose with MSV dosing regimen of vinorelbine.
Fig 4
Fig 4
Mean plasma concentration-time curves of OSI-420 (A) on Day 3 after initial oral dose with CSV dosing regimen of vinorelbine, (B) on Day 10 at the steady state after oral dose with CSV dosing regimen of vinorelbine, (C) on Day 3 after initial oral dose with MSV dosing regimen of vinorelbine and (D) on Day 10 at the steady state after oral dose with MSV dosing regimen of vinorelbine.
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