PK/PD modeling analysis for dosing regimen selection of isatuximab as single agent and in combination therapy in patients with multiple myeloma.

This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti-CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M-protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials.

Drug-Disease Interaction and Time-Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal "myeloma proteins" (M-proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)-mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1-20 mg/kg isatuximab either as single agent or in combination with pomalidomide-dexamethasone in 4 clinical trials.

Validation of Neutrophil Count as An Algorithm-Based Predictive Factor of Progression-Free Survival in Patients with Metastatic Soft Tissue Sarcomas Treated with Trabectedin.

: Based on a mathematical model of trabectedin-induced neutropenia, we assessed the predictive value of absolute neutrophil count (ANC) on progression-free survival (PFS) in an independent validation cohort of patients treated with trabectedin. : We collected data from 87 patients in two expert centers who received at least two cycles of trabectedin for soft tissue sarcomas (STS) treatment. Correlations between ANC, patients' characteristics, and survival were assessed, and a multivariate model including tumor grade, performance status, ANC, and hemoglobin level was developed.

Meningioma growth dynamics assessed by radiocarbon retrospective birth dating.

It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected.

Revisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non-Small Cell Lung Carcinoma.

Concomitant administration of bevacizumab and pemetrexed-cisplatin is a common treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). Vascular normalization following bevacizumab administration may transiently enhance drug delivery, suggesting improved efficacy with sequential administration. To investigate optimal scheduling, we conducted a study in NSCLC-bearing mice.

A multiscale modelling approach for the regulation of the cell cycle by the circadian clock.

We present a multiscale mathematical model for the regulation of the cell cycle by the circadian clock. Biologically, the model describes the proliferation of a population of heterogeneous cells connected to each other. The model consists of a high dimensional transport equation structured by molecular contents of the cell cycle-circadian clock coupled oscillator.

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

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.

Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis.

Bevacizumab is the first-in-class antiangiogenic drug and is almost always administrated in combination with cytotoxics. Reports have shown that bevacizumab could induce a transient phase of vascular normalization, thus ensuring a better drug delivery when cytotoxics administration is adjuvant. However, determining the best sequence remains challenging.

Implication of the Autologous Immune System in BCR-ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib.

Imatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts.