Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors.

Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.

Entinostat as a combinatorial therapeutic for rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1 ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis.

Quantitative determination of liposomal irinotecan and SN-38 concentrations in plasma samples from children with solid tumors: Use of a cryoprotectant solution to enhance liposome stability.

Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs.

Population pharmacokinetics of methotrexate and 7-hydroxymethotrexate and delayed excretion in infants and young children with brain tumors.

Purpose: The objectives of this study were to develop a population pharmacokinetic model of methotrexate (MTX) and its primary metabolite 7-hydroxymethotrexate (7OHMTX) in children with brain tumors, to identify the sources of pharmacokinetic variability, and to assess whether MTX and 7OHMTX systemic exposures were related to toxicity.

Methods: Patients received 2.5 or 5 g/m MTX as a 24-hour infusion and serial samples were analyzed for MTX and 7OHMTX by an LC-MS/MS method.

Effect of Obesity on the Pharmacokinetics and Pharmacodynamics of Anticancer Agents.

An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases.

Topotecan clearance based on a single sample and a population pharmacokinetic model: Application to a pediatric high-risk neuroblastoma clinical trial.

Background: Topotecan, an antitumor drug with systemic exposure (SE)-dependent activity against many pediatric tumors has wide interpatient pharmacokinetic variability, making it challenging to attain the desired topotecan SE. The study objectives were to update our topotecan population pharmacokinetic model, to evaluate the feasibility of determining individual topotecan clearance using a single blood sample, and to apply this approach to topotecan data from a neuroblastoma trial to explore exposure-response relationships.

Procedure: Our previous population pharmacokinetic and covariate model was updated using data from 13 clinical pediatric studies.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

Background: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.

Methods: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241).

CNS penetration of methotrexate and its metabolite 7-hydroxymethotrexate in mice bearing orthotopic Group 3 medulloblastoma tumors and model-based simulations for children.

The brain penetration of methotrexate (MTX) and its metabolite 7-hydroxymethotrexate (7OHMTX) was characterized in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. Plasma pharmacokinetic studies and cerebral and ventricular microdialysis studies were performed in animals dosed with 200 or 1000 mg/kg MTX by IV bolus. Plasma, brain/tumor extracellular fluid (ECF) and lateral ventricle cerebrospinal fluid (CSF) MTX and 7OHMTX concentration-time data were analyzed by validated LC-MS/MS methods and modeled using a population-based pharmacokinetic approach and a hybrid physiologically-based model structure for the brain compartments.

Development and Validation of a Sensitive and Specific LC-MS/MS Method for IWR-1-Endo, a Wnt Signaling Inhibitor: Application to a Cerebral Microdialysis Study.

IWR-1-endo, a small molecule that potently inhibits the Wnt/β-catenin signaling pathway by stabilizing the AXIN2 destruction complex, can inhibit drug efflux at the blood−brain barrier. To conduct murine cerebral microdialysis research, validated, sensitive, and reliable liquid chromatography−tandem mass spectrometry (LC-MS/MS) methods were used to determine IWR-1-endo concentration in the murine plasma and brain microdialysate. IWR-1-endo and the internal standard (ISTD) dabrafenib were extracted from murine plasma and microdialysate samples by a simple solid-phase extraction protocol performed on an Oasis HLB µElution plate.

Combination of Ribociclib and Gemcitabine for the Treatment of Medulloblastoma.

Group3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3MBs. Ribociclib central nervous system (CNS) penetration was assessed by in vivo microdialysis and by IHC and gene expression studies and found to be CNS-penetrant.

Phase I study of ribociclib and everolimus in children with newly diagnosed DIPG and high-grade glioma: A CONNECT pediatric neuro-oncology consortium report.

Background: Genomic aberrations in the cell cycle and PI3K/Akt/mTOR pathways have been reported in diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). Dual inhibition of and mTOR has biologic rationale and minimal overlapping toxicities. This study determined the recommended phase 2 dose (RP2D) of ribociclib and everolimus following radiotherapy in children with DIPG and HGG.

Population pharmacokinetics of crenolanib in children and young adults with brain tumors.

Purpose: Crenolanib, an oral inhibitor of platelet-derived growth factor receptor, was evaluated to treat children and young adults with brain tumors. Crenolanib population pharmacokinetics and covariate influence were characterized in this patient population.

Methods: Patients enrolled on this phase I study (NCT01393912) received oral crenolanib once daily.

Phase I study using crenolanib to target PDGFR kinase in children and young adults with newly diagnosed DIPG or recurrent high-grade glioma, including DIPG.

Background: Platelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).

Methods: We used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B).

Serial assessment of measurable residual disease in medulloblastoma liquid biopsies.

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial.

Population pharmacokinetic analysis of crizotinib in children with progressive/recurrent high-grade and diffuse intrinsic pontine gliomas.

Purpose: Crizotinib, a potent oral tyrosine kinase inhibitor, was evaluated in combination with dasatinib in a phase 1 trial (NCT01644773) in children with progressive or recurrent high-grade and diffuse intrinsic pontine gliomas (HGG and DIPG). This study aimed to characterize the pharmacokinetics of crizotinib in this population and identify significant covariates.

Methods: Patients (N = 36, age range 2.

Fusion Oncoproteins in Childhood Cancers: Potential Role in Targeted Therapy.

Cancer remains the leading cause of death from disease in children. Historically, in contrast to their adult counterparts, the causes of pediatric malignancies have remained largely unknown, with most pediatric cancers displaying low mutational burdens. Research related to molecular genetics in pediatric cancers is advancing our understanding of potential drivers of tumorigenesis and opening new opportunities for targeted therapies.

Development and validation of an LC-MS/MS method to quantify the bromodomain and extra-terminal (BET) inhibitor JQ1 in mouse plasma and brain microdialysate: Application to cerebral microdialysis study.

JQ1, is a cell-permeable small-molecule inhibitor of bromodomain and extra-terminal protein (BET) function with reportedly good CNS penetration, however, unbound and pharmacologically active CNS JQ1 exposures have not been characterized. Additionally, no quantitative bioanalytical methods for JQ1 have been described in the literature to support the CNS penetration studies. In the present article, we discuss the development and validation of a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative methods to determine JQ1 in mouse plasma and brain microdialysate.

Pharmacokinetically guided dosing of oral sorafenib in pediatric hepatocellular carcinoma: A simulation study.

Sorafenib improves outcomes in adult hepatocellular carcinoma; however, hand foot skin reaction (HFSR) is a dose limiting toxicity of sorafenib that limits its use. HFSR has been associated with sorafenib systemic exposure. The objective of this study was to use modeling and simulation to determine whether using pharmacokinetically guided dosing to achieve a predefined sorafenib target range could reduce the rate of HFSR.

Model-based evaluation of image-guided fractionated whole-brain radiation therapy in pediatric diffuse intrinsic pontine glioma xenografts.

Radiation therapy (RT) is currently the standard treatment for diffuse intrinsic pontine glioma (DIPG), the most common cause of death in children with brain cancer. A pharmacodynamic model was developed to describe the radiation-induced tumor shrinkage and overall survival in mice bearing DIPG. CD1-nude mice were implanted in the brain cortex with luciferase-labeled patient-derived orthotopic xenografts of DIPG (SJDIPGx7 H3F3A and SJDIPGx37 H3F3A ).

LC-MS/MS method for quantitation of gemcitabine and its metabolite 2',2'-difluoro-2'-deoxyuridine in mouse plasma and brain tissue: Application to a preclinical pharmacokinetic study.

A simple, sensitive, and relatively fast assay was developed and validated for the quantitation of gemcitabine (dFdC) and its major metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) in mouse plasma and brain tissue. The assay used a small sample (25 μL plasma and 5 mg brain) for extraction by protein precipitation. After dilution of the supernatant extract, 1 μL was injected into HPLC system for reverse phase chromatographic separation with a total run time of 8 min.