A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol

Our plain-English summary of A phase Ia/Ib clinical trial of metronomic chemotherapy based on a mathematical model of oral vinorelbine in metastatic non-small cell lung cancer and malignant pleural mesothelioma: rationale and study protocol, by X. Elharrar, D. Barbolosi, J. Ciccolini, et al (BMC Cancer, 2016).

The study

• Authors: X. Elharrar, D. Barbolosi, J. Ciccolini, C. Meille, C. Faivre, B. Lacarelle, N. André, F. Barlesi
• Journal: BMC Cancer
• Published: 2016;16:278
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Metronomic oral vinorelbine is effective in metastatic NSCLC and malignant pleural mesothelioma, but all the studies published thus far were based upon a variety of empirical and possibly suboptimal schedules, with inconsistent results. Mathematical modelling showed by simulation that a new metronomic protocol could lead to a better safety and efficacy profile.

Design: This phase Ia/Ib trial was designed to confirm safety (phase Ia) and evaluate efficacy (phase Ib) of a new metronomic oral vinorelbine schedule. Patients with metastatic NSCLC or malignant pleural mesothelioma in whom standard treatments failed and who exhibited ECOG performance status 0-2 and adequate organ function will be eligible. Our mathematical PK-PD model suggested an alternative weekly D1, D2 and D4 schedule (named Vinorelbine Theoretical Protocol) with a respective dose of 60, 30 and 60 mg. Trial recruitment will be two-staged, as 12 patients are planned to participate in phase Ia to confirm safety and consolidate the calibration of the model parameters. Depending on the phase Ia results and after a favourable decision from a consultative committee, the extension phase (phase Ib) will be an efficacy study including 20 patients who will receive the Optimal Vinorelbine Theoretical Protocol. The primary endpoint is the tolerance (assessed by CTC v4.0) for the phase Ia and the objective response according to RECIST 1.1 for phase Ib. An ancillary study on circulating angiogenesis biomarkers will be a subproject of the trial.

Discussion: This ongoing trial is the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy. As such, this trial can be considered as a proof-of-concept study demonstrating the feasibility to run a computational-driven protocol to ensure an optimal efficacy/toxicity balance in patients with cancer.

Trial Registration: EudraCT N°: 2015-000138-31.

In plain English

This article is a study protocol. It described a planned trial and reported no patient results. The authors planned a prospective, non-randomized phase Ia/Ib trial of oral vinorelbine, a chemotherapy drug, given on a 'metronomic' schedule. The schedule, called the Vinorelbine Theoretical Protocol, was chosen with the authors' mathematical model: 60 mg on day 1, 30 mg on day 2 and 60 mg on day 4, every week. The trial was expected to enrol 32 adults with metastatic non-small cell lung cancer or malignant pleural mesothelioma whose disease had progressed after standard treatments. Twelve patients would take part in phase Ia to confirm safety. A phase Ib efficacy stage with 20 patients would follow only if a monitoring committee made a favourable decision after phase Ia. In computer simulations, the model predicted tolerance similar to an earlier schedule (50 mg on days 1, 3 and 5) but a greater effect on tumour growth, with less variability. The article did not study asbestos exposure. The authors described the trial as the first to prospectively test a mathematically optimized metronomic schedule. They noted that efficacy results may depend on the proportion of each disease among patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Study protocol for a prospective, non-randomized phase Ia/Ib trial of single-agent oral metronomic vinorelbine (phase Ia: safety; phase Ib: efficacy, conditional on a favourable monitoring committee decision); no results reported
• Who was studied: Planned: 32 adults with histologically or cytologically proven metastatic non-small cell lung cancer (NSCLC) or malignant pleural mesothelioma (MPM) whose disease progressed after standard treatments. Twelve would be in phase Ia, and 20 in phase Ib if the monitoring committee approved the second stage. The trial was at a phase I oncology unit in Marseille, France.
• Exposure: Treatment, not asbestos exposure: oral vinorelbine 60 mg on day 1, 30 mg on day 2 and 60 mg on day 4, weekly (Vinorelbine Theoretical Protocol), with a possibly refined optimal schedule in phase Ib
• Main results:
  • No trial results were reported. In the authors' model simulations, the Vinorelbine Theoretical Protocol was predicted to have similar tolerance to the Briasoulis et al. schedule (50 mg on days 1, 3 and 5) but a greater impact on tumour growth, with less variability
  • Moving to the second stage (phase Ib, 20 patients) was planned to happen only after a favourable decision by the monitoring committee
• The authors' conclusion: The authors described this ongoing trial as the first to prospectively test a mathematically optimized schedule in metronomic chemotherapy
• Limitations the authors state:
  • Because the trial includes both MPM and metastatic NSCLC, efficacy results may depend on the proportion of each disease among the patients

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Chemotherapy, Vinorelbine, Non-Small Cell Lung Cancer, Pleural Mesothelioma, ECOG Performance Status, Angiogenesis, Biomarker.

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