Ndepth: Novel Dose Escalation to Predict Treatment with Hydroxyurea
Authors: George Alex , Dinu Bogdan R. , Ware Russell E. 
Published: October 2019

Several clinical trials have demonstrated that hydroxyurea therapy offers significant benefits for infants, children, and adolescents with sickle cell anemia. Patients on hydroxyurea who achieve a stable maximum tolerated dose (MTD), defined by a target level of mild marrow suppression, have greater laboratory and clinical benefits than those maintained on a lower dose. A complicating factor in achieving MTD is the significant inter-patient variability in MTD, but no way currently to predict the MTD for individual patients. As such, MTD is commonly achieved by gradual dose escalation in a resource-intensive process that often takes six to twelve months and delays optimal treatment benefits.

Using published data from a cohort of previously untreated patients escalated to hydroxyurea MTD, we developed an equation to predict individualized MTD for patients initiating therapy. The primary objective of the Novel Dose Escalation to Predict Treatment with Hydroxyurea (NDEPTH, ClinicalTrials.gov 02042222) clinical trial is to determine the safety and efficacy of the dose-prediction equation. The study is designed as a prospective, open-label, randomized controlled trial consisting of two treatment arms: a Standard Treatment Arm utilizing a current published dose-escalation protocol for achieving hydroxyurea MTD and an Alternative Treatment Arm utilizing a dose-prediction equation to determine MTD, calculated prior to initiation of treatment. The primary endpoint of the study will be time to MTD for each arm. Additional endpoints include analyses of safety and biological responses to hydroxyurea therapy

At the planned interim analysis of this study, we have recruited ten participants to each arm of the study. Kaplan-Meier analysis of these twenty participants indicates that there is a trend approaching significance (p = 0.071) for subjects on the dose-prediction arm to reach MTD faster than those on the dose-escalation arm, with a median time to MTD of 112 days versus 309 days respectively. Additionally, the dose-prediction equation has a high degree of accuracy (R2 = 0.66; p = 0.001) in predicting the actual MTD for all enrolled participants, with a mean predicted dose of 26.4 ± 1.6 mg/kg and actual dose of 27.1 ± 4.1 mg/kg. Children on the dose-prediction Alternative Treatment Arm have had a higher incidence of excessive myelosuppression requiring temporary dose cessation in three subjects, but no clinical adverse events. These interim results suggest that the dose-prediction equation is safe and effective in determining MTD for young patients with SCA initiating hydroxyurea therapy. Final analysis of the safety and efficacy of the dose-prediction equation will be performed upon completion of the study.

Disclosures

Off Label Use: This abstract describes the use of hydroxyurea in pediatric sickle cell patients. Hydroxyurea is not currently approved by the FDA for this purpose.. Ware:Bayer Pharmaceuticals: Consultancy; Eli Lilly: Other: DSMB membership; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding.