Improving Pediatric Hematology Oncology Outcomes Through Precision Medicine and Experimental Therapeutics

Clinical Pharmacology Expertise Advances Understanding of Pediatric Dosing

Precision in oncology medication dosing is crucial for treatment effectiveness. Most of what doctors know about oncology medications, however, is based on adult dosing. Because children metabolize medications differently than adults, dosing can be ineffective when approached in this manner.

Jaszianne Tolbert, MD, Director of Experimental Therapeutics in Pediatric Cancer at Children’s Mercy Kansas City, is focused on improving outcomes and decreasing treatment-related mortality in childhood cancer through pharmacokinetic and pharmacogenomic-guided dose individualization. As one of the few pediatric hematologists/oncologists nationwide who is also fellowship-trained in clinical pharmacology, Dr. Tolbert is uniquely qualified for this role.

Children’s Mercy is home to the largest pediatric pharmacology program in North America and is one of only a few hospitals with a pediatric hematologist/oncologist also trained in clinical pharmacology.

GOLDILOKs: A Framework for Clinical Study Design

Dr. Tolbert is developing clinical trials using the Genomic and Ontogeny Linked Dose Individualization and Clinical Optimization for Kids (GOLDILOKs®) program. Developed by Steven Leeder, PharmD, PhD, Marion Merrell Down Endowed Chair in Pediatric Precision Therapeutics, and Deputy Director of the Children’s Research Institute, GOLDILOKs is a conceptual framework that helps researchers appropriately develop clinical trials to optimize medication dosing for children.

GOLDILOKs helps clinical pharmacologists, physicians and other providers more precisely personalize care for their patients and provide more effective care by delivering the best medication in the dose that is just right for each individual child.

Population-based Pharmacokinetic Modeling

Currently, most dosing is based on body weight. This method doesn’t account for actual drug exposure, which is affected by the way each patient metabolizes the drug. As a result, patients may receive too much, resulting in toxicity, or may receive too little, which detracts from the desired therapeutic outcome.

Dr. Tolbert is currently working with Dr. Leeder and others to design population-based pharmacokinetic modeling with a focus on leukemia drugs. Once development is complete, clinicians will be able to enter a patient’s unique characteristics -- such as genetics, age, weight, type of cancer and that cancer’s unique mutation -- that may play a role in how patients metabolize drugs. This more tailored approach will ensure more appropriate dosing.

Real-time Impact on Busulfan Dosing

One of the early applications of the GOLDILOKs initiative was to effectively determine Busulfan dosing in pediatric bone marrow transplant patients. Susan Abdel-Rahman, Pharm D, Section Chief, Therapeutic Innovation, led a team that built a Bulsulfan decision-support tool that provides clinicians real-time drug exposure data, via a blood test, after they give a patient a dose of the drug. Using GOLDILOKs and its decision-support capabilities, the doctor can modify the next dose to ensure the patient receives the right concentration.

Study Looks at Obese Patients with ALL

In another recent study, Dr. Tolbert and team looked at the impact of obesity and xanthine oxidase phenotype on 6-MP disposition in children with acute lymphoblastic leukemia (ALL). Early findings show that kids who are obese have higher levels of the drug metabolizing enzyme that produces the inactive metabolite, resulting in lower drug exposure. Based on findings from this study, the team is now developing a new study to look closely at the drug clearance pathway and alter the current dosing to help kids achieve remission.

Partnership with University of Kansas Accelerates Drug Trials

As the official pediatric partner for the NCI-designated University of Kansas Cancer Center, the Experimental Therapeutics program at Children’s Mercy makes the most cutting-edge cancer therapies and clinical trials available to its patients. The two organizations closely collaborate to generate research ideas. Dr. Tolbert is a member of the Drug Discovery, Delivery & Experimental Therapeutics (D3ET) Research Program, led by the cancer center. The aim of this group is to:

• Discover novel anticancer drugs active against novel drug targets.
• Repurpose drugs, finding new indications for currently marketed drugs.
• Apply drug delivery platform technologies to improve the safety and/or efficacy of currently marketed anticancer agents.

Drug trials for adults begin at the cancer center, and the close collaboration with Children’s Mercy accelerates the move to pediatric studies.

Study Leads to Success with CART-19 in Treatment-resistant Leukemia

In 2010, Children’s Mercy was selected as the second site in the nation to participate in a study investigating the safety and efficacy of the immunotherapy agent CART-19. The team, led by Doug Myers, MD, Director of the Children’s Mercy Cellular Therapy Program, designed a process for taking a sample of a patient’s T cells, reengineering them to attack cancer cells, and re-implanting them in the patient. Response rates in certain forms of treatment-resistant leukemia were as high as 85 to 90 percent.

Learn more about precision medicine and experimental therapeutics
Jaszianne Tolbert, MD, Director of Experimental Therapeutics
Jtolbert1@cmh.edu
(816) 302-6808

transformpeds.childrensmercy.org

For consults, admissions or transport call: 1 (800) GO MERCY/1 (800) 466-3729.