Studies of the clinical pharmacology of anticancer drugs used to treat childood cancers focus on new drug development and on the design of more rational approaches to the use of these agents based on the study of their pharmacokinetics and pharmacodynamics. The central nervous system (CNS) pharmacology of anticancer drugs and the identification of new treatment approaches for CNS tumors are emphasized. An integrated research program, which includes preclinical models to study the pharmacology of novel agents and an active clinical trials program to study the toxicity, activity, and clinical pharmacology of these agents in children, is utilized. The CNS pharmacology of anticancer drugs is studied in a non-human primate model with indwelling ventricular catheters that allow for drug instillation into the ventricle and sampling of the cerebrospinal fluid (CSF). Drug penetration into the CSF, which serves as a surrogate measure of blood-brain barrier (BBB) penetration, is used to identify potential new drugs for CNS tumors. Drug penetration into brain and other tissues is also being studied using microdialysis. In addition, new strategies to pharmacologically modulate the BBB are being investigated in this model. The preclinical and clinical development of new agents that can be administered intrathecally for the treatment of meningeal tumors is another focus of research. In addition to its role in studying the CNS pharmacology of anticancer drugs, microdialysis is also being investigated as a tool to quantify drug concentrations in tumors in animal models and eventually in humans. Clinical trials are performed as single institution studies or collaboratively with other children's cancer centers or Children's Oncology Group. A variety of agents are studied, including classical cytotoxic drugs, drugs with novel mechanisms of action (molecularly targeted drugs), and agents that modulate the effect of anticancer drugs (e.g., reverse drug resistance). Novel clinical trial designs are developed to optimally study new agents in children. Clinical pharmacokinetic studies focus on the development of pharmacokinetic models that allow for simulation of other doses and schedules, development of limited sampling strategies to simplify drug monitoring, and correlation with pharmacodynamic parameters, such as toxicity or response. Pharmacokinetic studies are being performed on a number of adult clinical trials in collaboration with investigators in the Medicine and Surgery Branches. New approaches to imaging and monitoring response in CNS tumors utilizing nuclear magnetic resonance spectroscopy and 3-dimensional image analysis, are incorporated into clinical brain tumor trials.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006880-24
Application #
6558382
Study Section
(POB)
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Fox, Elizabeth; Widemann, Brigitte C; Chuk, Meredith K et al. (2013) Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 19:4239-48
Widemann, Brigitte C; Goodspeed, Wendy; Goodwin, Anne et al. (2009) Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors. J Clin Oncol 27:550-6
Abraham, Jame; Edgerly, Maureen; Wilson, Richard et al. (2009) A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clin Cancer Res 15:3574-82
Kim, AeRang; Balis, Frank M; Widemann, Brigitte C (2009) Sorafenib and sunitinib. Oncologist 14:800-5
Chuk, Meredith K; Balis, Frank M; Fox, Elizabeth (2009) Trabectedin. Oncologist 14:794-9
Balis, F M; Fox, E; Widemann, B C et al. (2009) Clinical drug development for childhood cancers. Clin Pharmacol Ther 85:127-9
Kim, Aerang; Fox, Elizabeth; Warren, Katherine et al. (2008) Characteristics and outcome of pediatric patients enrolled in phase I oncology trials. Oncologist 13:679-89
Jacobs, Shana S; Stork, Linda C; Bostrom, Bruce C et al. (2007) Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer 49:250-5
Adamson, Peter C; Matthay, Katherine K; O'Brien, Michelle et al. (2007) A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study. Pediatr Blood Cancer 49:661-5
Widemann, Brigitte C; Salzer, Wanda L; Arceci, Robert J et al. (2006) Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol 24:507-16

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