Sunitinib is the most commonly prescribed drug for advanced
renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on-and off-target effects, including hand and foot syndrome and
fatigue. It was hypothesized that
sunitinib-induced
fatigue may be related to off target inhibition of the AMPK
enzyme, which results in impairment of energy-producing processes at a systemic level.
Quercetin is a naturally occurring
flavonol with established AMPK-stimulating activity. While clinical use of
quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is
isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral
isoquercetin could improve
fatigue in
kidney cancer patients receiving
sunitinib. Given the lack of data on the safety of
isoquercetin given concomitantly with
sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured
isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study,
isoquercetin was administered concomitantly with 50 mg
sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required
isoquercetin suspension or
isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT
fatigue score (6.8 points; 95% CI: 2.8-10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1-28.8; p < 0.001) after
isoquercetin consumption vs. baseline. In this phase I trial,
isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of
sunitinib adverse events.