Phase 1 study of quercetin, a natural antioxidant for children and young adults with Fanconi anemia

Abstract

Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure (BMF) and a predisposition to malignancy. Systemic reactive oxygen species (ROS) and increased sensitivity of FA hematopoietic progenitors to ROS play a key role in the pathogenesis of BMF. Treatment with antioxidants improve hematopoietic function in Fancc-/- mice. We report the safety, tolerability, and pharmacokinetics of quercetin, a naturally occurring antioxidant in the first dose-finding phase 1 study for patients with FA. Twelve patients (median age, 7 years [range, 3-21]) received oral quercetin twice daily for 4 months. Quercetin was well tolerated at all dose levels. Allometrically bodyweight-adjusted dose with a maximum adult daily dose of 4000 mg/d was established as the recommended dose of quercetin. Patients in an expansion cohort (n = 18) were treated using this recommended dose for 6 months. A subset of patients showed reduced ROS levels in the peripheral blood (PB) and bone marrow stem cell compartment. Patients in the analysis cohort treated with the recommended dose of quercetin achieved an a priori-defined optimal response of 25% reduction in the PB ROS level compared with baseline. Platelet counts remained stable to slightly improved over the study period (P = .06). Absolute neutrophil counts (P = .01) and hemoglobin levels gradually declined (P = .001). In those with evidence of BMF at baseline, 8 of 15 patients (53%) had a hematological response at some point after quercetin treatment. Fluctuations in counts are common in patients with FA, limiting accurate assessment of the impact of quercetin use in FA. This trial was registered at www.ClinicalTrials.gov as #NCT01720147.

Graphical abstract

Figure 1.

Study population enrolled and duration of protocol treatment. In dose-finding phase, 12 patients received oral quercetin twice a day for 4 months (16 weeks). An optional 20-month continuation phase at the assigned dosing was offered to those who wished to continue after completion of the first 4 months. In expansion cohort, 18 patients were treated with quercetin for 6 months at the recommended weight-adjusted dose identified in the dose-finding phase 1 study. Those who wished to continue quercetin beyond 6 months were treated for an additional 6 months for a total of up to 1 year. In analysis cohort, 21 patients (last 3 patients from the phase 1 cohort and 18 from the expansion cohort) treated with quercetin at the recommended dosing were included in this cohort. Max, maximum.

Figure 2.

Quercetin PK parameter estimates after first dose and at 4 months after multiple doses of quercetin in 8 pediatric patients receiving powder form. (A) Quercetin PK profiles show wide interindividual variability in absorption. (B) Quercetin PK parameter estimates. No significant differences were observed in Cmax, Tmax, and t½ between day 1 levels after a single dose of quercetin and at 4 months after multiple doses. Quercetin accumulation was not observed after 4 months of administration. Significantly higher clearance (CL/F; P < .01) and Vd/F (P < .01) were observed at 4 months after quercetin compared with the initial dose. (C) Quercetin dose escalation based on PKs and identification of the recommended dose. The first 3 patients underwent intrapatient dose escalation to a maximum of 1500 mg/d. Subsequent cohorts (3 patients each) were treated with escalating doses based on tolerability, safety, and quercetin exposure in the previous cohort. A weight-adjusted daily maximum dose of 4000 mg/d was considered the recommended dose and was selected for treatment of patients in the expansion cohort. Our PK model predicted no further increase in quercetin exposure beyond what is achieved by the currently recommended dose, likely because of enterohepatic circulation and first-pass metabolism.

Figure 3.

Total PB ROS levels in patients with FA after quercetin treatment (phase 1 dose-finding cohort and analysis cohort). (A) Total PB ROS levels in individual patients (phase 1 cohort). Seven of 12 patients (58%) experienced decrease in PB ROS at 4 months, and 7 of 9 patients (78%) showed decrease in PB ROS at 1 year (3 patients came off study before 1 year). Note: patients in each cohort received escalating doses of quercetin. The last 3 patients treated at the daily maximum dose of 4000 mg/d achieved the highest and most consistent ROS reduction. (B) Median total PB ROS levels in all patients (phase 1 cohort). As desired, median total PB ROS levels decreased after 4 months of treatment with quercetin (42.5% reduction; P = .23). In 9 patients with available PB ROS results, median ROS levels decreased at 1 year (75% reduction; P = .04). (C) Median total PB ROS levels in all patients (analysis cohort). Median total PB ROS levels decreased by 25% at 6 months (P = .67) and 18% at 1 year (P = .06) compared with baseline after treatment with quercetin.

Figure 4.

Peripheral counts after treatment with quercetin (analysis cohort). Median platelet counts increased at 2 and 4 months after treatment with quercetin, remained stable at 6 months, and increased again at 1 year (P = .06) compared with baseline. Median ANC improved at 2 and 4 months, remained stable at 6 months, and decreased at 1 year (P = .01). Median Hb remained stable at 2 and 4 months and decreased at 6 months and 1 year (P < .001) after quercetin. Hb, hemoglobin.