Revisiting metronomic vinorelbine with mathematical modelling: a Phase I trial in lung cancer.

BACKGROUND: A phase Ia/Ib trial of metronomic oral vinorelbine (MOV) driven by a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Disease Control Rate, progression free survival, toxicity and PK/PD were the main endpoints. METHODS: Best MOV scheduling was selected using a simplified phenomenological, semi-mechanistic model with a total weekly dose of 150-mg vinorelbine. Computation of individual PK parameters was performed using population approach. RESULTS: The mathematical model proposed the following metronomic schedule for a 150-mg weekly dose of vinorelbine: 60 mg D1, 30 mg D2, 60 mg D4. A total of 37 heavily pre-treated patients (30 evaluable) were enrolled. Grade III/IV neutropenia was observed in 30% patients. Median PFS was 11 weeks. Disease Control Rate was 73% (i.e.; 13% partial response and 60% stable disease). A large variability in drug exposure (AUC0-24 h: 53%) and PK parameters (Cl: 83%) were observed among patients. Simulated trough levels after D2 and D4 showed similarly 56-73% variability among patients. Drug exposure was not associated with efficacy, but neutropenia was more frequent in patients with AUC > 250 ng/ml.h. Tumor burden, performance status and neutrophils-to-lymphocyte ratio (NLR) were associated with PFS, suggesting that MOV would be indicated in selected patients. We built a composite score to predict efficacy, mixing baseline tumor size and NLR showing 84% selectivity and 75% specificity. CONCLUSIONS: MOV was characterized by important variability in drug exposure among patients. However, and despite being all heavily pre-treated, 73% of disease control rate and 11 weeks PFS were achieved with manageable toxicities. PK/PD relationships yielded conflicting results depending on the initial tumor burden and BSA, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker suggests immunomodulating features with MOV.

Mathematical modeling of peripheral blood neutrophil kinetics to predict CLAD after lung transplantation.

BACKGROUND: The presence of neutrophils in the lung was identified as a factor associated with CLAD but requires invasive samples. The aim of this study was to assess the kinetics of peripheral blood neutrophils after lung transplantation as early predictor of CLAD. METHODS: We retrospectively included all recipients transplanted in our center between 2009 and 2014. Kinetics of blood neutrophils were evaluated to predict early CLAD by mathematical modeling using unadjusted and adjusted analyses. RESULTS: 103 patients were included, 80 in the stable group and 23 in the CLAD group. Bacterial infections at 1 year were associated with CLAD occurrence. Neutrophils demonstrated a high increase postoperatively and then a progressive decrease until normal range. Recipients with CLAD had higher neutrophil counts (mixed effect coefficient beta over 3 years = +1.36 G/L, 95% Confidence Interval [0.99-1.92], p < .001). A coefficient of celerity (S for speed) was calculated to model the kinetics of return to the norm before CLAD occurrence. After adjustment, lower values of S (slower decrease of neutrophils) were associated with CLAD (Odds Ratio = 0.26, 95% Confidence Interval [0.08-0.66], p = .01). CONCLUSION: A slower return to the normal range of blood neutrophils was early associated with CLAD occurrence.