Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning.

Aim: To evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT).

Methods: This study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.

Tyrosine kinase inhibitors in cancers: Treatment optimization - Part II.

Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects.

Tyrosine kinase inhibitors in cancers: Treatment optimization - Part I.

A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase.

Pegylated liposome encapsulating docetaxel using microfluidic mixing technique: Process optimization and results in breast cancer models.

The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications.

Overcoming immuno-resistance by rescheduling anti-VEGF/cytotoxics/anti-PD-1 combination in lung cancer model.

Many tumors are refractory to immune checkpoint inhibitors, but their combination with cytotoxics is expected to improve sensitivity. Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors. studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model.

Killing a fly with a sledgehammer: Atezolizumab exposure in real-world lung cancer patients.

Atezolizumab is an anti-PDL1 approved for treating lung cancer. A threshold of 6 μg/mL in plasma has been associated with target engagement. The extent to which patients could be overexposed with the standard 1200 mg q3w dosing remains unknown.

Life-threatening toxicities upon Pembrolizumab intake: could pharmacokinetics be the bad guy?

Purpose: We report the case of an adult patient diagnosed with Hodgkin's lymphoma who was scheduled for Pembrolizumab after failure of standard therapy. After three well-tolerated courses of Pembrolizumab, a PET scan showed a favorable outcome and a fourth course of Pembrolizumab was started. Unexpectedly, extremely severe toxicities (i.

Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients.

Azacitidine (Aza) is a mainstay of treatment for patients with acute myeloid leukaemia (AML) ineligible for induction chemotherapy and other high-risk myelodysplastic syndromes (MDS). Only half of patients respond, and almost all will eventually relapse. There are no predictive markers of response to Aza.

Pancreatic ductal adenocarcinoma ubiquitination profiling reveals specific prognostic and theranostic markers.

Background: Pancreatic ductal adenocarcinoma (PDAC) has been widely studied at multiomics level. However, little is known about its specific ubiquitination, a major post-translational modification (PTM). As PTMs regulate the final function of any gene, we decided to establish the ubiquitination profiles of 60 PDAC.

A non-inferiority randomized phase III trial of standard immunotherapy by checkpoint inhibitors vs. reduced dose intensity in responding patients with metastatic cancer: the MOIO protocol study.

Background: Immunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy.

Machine-Learning Exploration of Exposure-Effect Relationships of Cisplatin in Head and Neck Cancer Patients.

Background: Cisplatin is a pivotal drug in the treatment of head and neck cancer, and personalized dosage should help the preservation of an optimal toxicity-efficacy ratio.

Methods: We analyzed the exposure-effect relationships of 80 adult patients with head and neck cancers and treated with standard Cisplatin-based regimen administered as three-hour infusion. Individual pharmacokinetics (PK) parameters of Cisplatin were identified using a Bayesian approach.

Tumor growth monitoring in breast cancer xenografts: A good technique for a strong ethic.

Purpose: Although recent regulations improved conditions of laboratory animals, their use remains essential in cancer research to determine treatment efficacy. In most cases, such experiments are performed on xenografted animals for which tumor volume is mostly estimated from caliper measurements. However, many formulas have been employed for this estimation and no standardization is available yet.

Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency.

Aims: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH ) concentrations, as they are essential in reliable DPD-deficiency testing.

Methods: U and UH concentrations were collected from 14 hospital laboratories.

Renal impairment and DPD testing: Watch out for false-positive results!

Measuring uracil (U) levels in plasma is a convenient surrogate to establish dihydropyrimidine dehydrogenase (DPD) status in patients scheduled with 5-fluorouracil (5-FU) or capecitabine. To what extent renal impairment could impact on U levels and thus be a confounding factor is a rising concern. Here, we report the case of a cancer patient with severe renal impairment scheduled for 5-FU-based regimen.

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.

Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model-based population pharmacokinetic analysis.

Purpose: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients.

Design/methods: We collected blood samples from 36 patients (mean age 11.

Potential Role of Exosomes in the Chemoresistance to Gemcitabine and Nab-Paclitaxel in Pancreatic Cancer.

In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel.

Adaptive dosing of sunitinib in a metastatic renal cell carcinoma patient: when in silico modeling helps to go quicker to the point.

Purpose: Adaptive dosing strategy with oral targeted therapies in oncology is mostly based upon clinical signs. Using pharmacokinetics (PK) models to customize dosing could help saving time, i.e.

Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study.

Background: Different liquid chromatography tandem mass spectrometry (LC-MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC-MS/MS method using a ready-to-use kit to simultaneously assay 7 mAbs (i.e.

Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351.

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351.