Design of an Ongoing Phase I/II Open-Label, Dose-Escalation Trial Using the Oral Chelator Deferasirox To Treat Iron Overload in HFE-Related Hereditary Hemochromatosis (HH).
Authors: Pietrangelo A. , Brissot P. , Bonkovsky H. , Niederau C. , Rojkjaer L. , Weitzman R. , Bodner J. , Bailey S. , Phatak Pradyumna D. 
Published: April 2020

Abstract
HH is a genetic disorder commonly associated with homozygosity for the C282Y HFE mutation and characterized by progressive iron overload through increased intestinal absorption. Organ failure due to iron toxicity may develop. Iron removal by phlebotomy is the preferred treatment and has been demonstrated to prevent or reverse some of the complications of iron overload. However, compliance with a weekly phlebotomy schedule is variable, and some patients are ineligible for phlebotomy due to underlying medical disorders. Thus, if an oral iron chelator such as deferasirox proves to be safe and effective, HH patients will have an alternative treatment option. This is an inter-patient dose-escalation study of deferasirox (5, 10, 15, 20 mg/kg) given daily for 24 weeks to C282Y homozygous HH patients with a pre-treatment serum ferritin (SF) value ≥300 μg/L and ≤2000 μg/L, and transferrin saturation ≥45%. Major exclusion criteria are men with hemoglobin &lt;13 g/dL, women with hemoglobin &lt;12 g/dL, a history of blood transfusion during 6 months prior to study entry, serum creatinine above the upper limit of normal (ULN), and serum ALT ≥2xULN at screening. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include the change in SF from baseline at 24 weeks, the time to normalization of SF (defined as the first occurrence of reduction of SF to &lt;100 μg/L), the longitudinal course of SF, and the pharmacokinetics of deferasirox. It is estimated that at least 40 patients are needed to evaluate safety at all dose levels. Cohorts of 8 patients per dose level will be used in order to detect AEs with a 25% true incidence rate at that dose with 90% power. Safety monitoring will be based on medical review and a 2-parameter Bayesian logistic regression model for dose-dependent probabilities of a severe AE. To assess efficacy, the change from baseline in SF after 24 weeks of treatment will be analyzed by performing an analysis of covariance (ANCOVA). To date, 11 patients (9 men, 2 women; all Caucasian; mean age 56 years) with a mean of 7 years since HH diagnosis have been treated at 5 mg/kg/day for at least 4 weeks. There was a mean of 7 years since HH diagnosis, with 2 patients not having been previously treated. The remaining 9 had been treated with phlebotomy, one of whom had also been treated with deferoxamine. Baseline iron studies and ALT values for the 11 patients treated at 5 mg/kg/day are summarized in the table. The dose of deferasirox has been escalated to 10 mg/kg/day after no patients were seen to experience severe AEs at 5 mg/kg/day. In conclusion, this ongoing study will generate preliminary safety and efficacy data for deferasirox use in iron-overloaded HH patients, indicating whether deferasirox could be an alternative to phlebotomy in selected patients.
Parameter n Mean±SD Median Range Normal range SF, ng/mL 11 633.0±428.9 567.0 350–1880 30–400 (men); 15–150 (women) Transferrin saturation, % 11 75.5±19.6 82.0 39–95 20–55 ALT, U/L 11 43.4±33.4 34.0 8–122 0–45