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

Abstract

BackgroundMetronomic 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.DesignThis 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.DiscussionThis 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 registrationEudraCT N°: 2015-000138-31

Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer

“…This study, as well as others based on a mathematical model, revealed that oral mVNR in elderly patients showed long-term disease stabilization and optimal patient compliance in elderly patients [ 22 – 25 ]. Furthermore, several lines of evidence demonstrated that vinorelbine improves survival in elderly patients and quality of life (QoL) [ 26 ].…”

Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy

“…Collectively, our results suggest that our pharmacokinetic/ pharmacodynamic model could be a useful tool for in silico simulations to identify the best modalities for metronomic administration to be tested in priority in nonclinical models, thus avoiding testing regimens that are likely to fail in the clinic. This model has now been used with metronomic temozolomide in glioma (14), metronomic vinorelbine in lung cancer (23), and metronomic gemcitabine in neuroblastoma, but it could also be applied to other drugs commonly used in metronomic protocols, such as cyclophosphamide, capecitabine, and etoposide, provided that extensive pharmacokinetic/pharmacodynamic data are generated and made available. Overall, our study indicates that phenomenological mathematical modeling could help guide optimal dosing and scheduling of chemotherapy.…”

“…First built for the metronomic administration of temozolomide (14), our model allows in silico predictions that can mimic clinical situations and provide clues for the optimization of the metro-nomic protocol in this setting. The model was then adapted to the metronomic administration of vinorelbine and suggested an alternative schedule likely to be more efficacious while being well tolerated, as compared with empirical metronomic regimens described in the literature (23). An innovative phase I/II clinical trial of a metronomic vinorelbine regimen based on this mathematical model is currently ongoing in lung cancer patients (NCT02555007).…”

Next generation metronomic chemotherapy—report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6–8 May 2016, Mumbai

“…An on-going clinical trial is assessing the toxicity and scheduling of metronomic oral vinorelbine in non-small cell lung cancer based on such a model (NSCLC) [27]. Mathematics has also been used to support other novel approaches, for example ‘adaptive therapy’, in which treatment is tailored to tumour response, is driven by evolutionary modelling [28].…”