Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients

// Fabrice Barlesi 1, 2 , Diane-Charlotte Imbs 2 , Pascale Tomasini 1 , Laurent Greillier 1 , Melissa Galloux 1 , Albane Testot-Ferry 1 , Melanie Garcia 3 , Xavier Elharrar 1 , Annick Pelletier 1 , Nicolas Andre 2, 4 , Celine Mascaux 1 , Bruno Lacarelle 2, 3 , Raouf El Cheikh 2 , Raphael Serre 2 , Joseph Ciccolini 2, 3 and Dominique Barbolosi 2 1 Aix Marseille University, APHM, Marseille Early Phases Cancer Trials Center CLIP, Marseille, France 2 Aix Marseille University, SMARTc Unit, INSERM U911, Marseille, France 3 Aix Marseille University, APHM, Department of Pharmacology, Marseille, France 4 Aix Marseille University, APHM, Department of Pediatric Hematology and Oncology, Marseille, France Correspondence to: Fabrice Barlesi, email: fabrice.barlesi@ap-hm.fr Keywords: lung cancer, mesothelioma, mathematical modeling, vinorelbine, metronomic Received: March 24, 2017      Accepted: April 19, 2017      Published: May 02, 2017 ABSTRACT Introduction: Using mathematical modelling allows to select a treatment’s regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. Results: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1–32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine’s AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). Materials and Methods: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. Conclusions: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.