1. Jamie L. Renbarger, MD, MSApril 25, 2011 Optimizing Vincristine Dosing for Children Indiana CTSI Retreat 2011

2. 5/5/2015 2 Vincristine is the most commonly used pediatric anticancer agent Uses –Childhood ALL –Lymphoma –Wilms –Pediatric sarcomas –Pediatric brain tumors Toxicities –Neuropathy –Severe vesicant –SIADH –Alopecia –Minimal hematologic toxicity

3. Clinical Biomarkers of CIPN Age Race Treatment schedule Cumulative chemotherapy dose Concomitant medications Baseline peripheral neuropathy

4. Caucasians and low CYP3A5 expressers experience more VIPN 34.8% of Caucasians vs. 4.5% of African- Americans with ALL (p=0.004) Cumulative VIPN score greater in low CYP3A5 expressers: 13.9 ± 11.2 vs. 7.2 ± 5.5 (p=0.0003) Renbarger JL et al. Pediatr Blood Cancer 2008 Apr;50(4):769-71. Egbelakin A, Ferguson M et al. Pediatr Blood Cancer 2011 Mar;56(3):361-7. PMID: 21225912

5. Dose-corrected M1 concentration associated with age and CYP3A5 p= 0.0033 Lehmann AS et al. 2010 ASCO # 9523 Black = CYP3A5 *0*0 Red = CYP3A5 *1*0 Green = CYP3A5*1*1

6. NOT-RR-09-005 Administrative Supplements for Research on Outcome Measures for Pediatric Clinical Trials in support of the BPCA Purpose…to stimulate collaborative, multidisciplinary basic and clinical research to: 1)Facilitate development of qualified outcome measures 2)Relate non-clinical to clinical outcome assessments in child health for improving the evaluation of interventions 3)Assess and interpret clinical outcomes

7. The Next Step Toward Optimization of Vincristine Dosing ADVANCE Multicenter trial: IU, UM, CNMC, VU –Enroll kids at time of diagnosis and prospectively follow them –Neuropathy phenotype: TNS and NPS (CTSI supplement award) –Vincristine pathway PG, PK, modeling (RC1) Vincristine PG in Kenyan children

8. Goal: optimize vincristine dosing Build a prediction model of vincristine neuropathy: –Clinical data –Disease data –Vincristine metabolomics/PK –Vinca pathway genomics

9. PROPEL Indiana University Children’s National Medical Center University of Michigan Vanderbilt University

10. Acknowledgements Indiana University Division of Clinical Pharmacology Jennifer Dennison Sara Quinney Lang Li David Flockhart Stephen Hall Section of Pediatric Hematology/Oncology, Indiana University Amalia Lehmann Akinbode Egbelakin Michael Ferguson Ariel Topletz Joy Rupenthal/Nicole Robinson Cindy Elkins Anne Bubnick IU Simon Cancer Center Clinical Pharmacology Analytic Core Laboratory David Jones Andi Masters University of Michigan Raymond Hutchinson Ellen Smith Children’s National Medical Center Roger Packer Vanderbilt University Richard Ho NIH 1RC1CA146882 UL1 RR 025761-02S5 NIH K23 RR019956 IUPUI Biomedical Research Grant Showalter Research Trust Fund Clarian Values Fund for Research