Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First-line Sunitinib: a Phase I/II Trial

Sunitinib is an oral receptor tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptors (VEGFRs), platelet derived growth factor receptor (PDGFRs) and c-kit. Sunitinib was the first TKI to be approved for the first-line treatment of advanced kidney cancer on the grounds of the results achieved in the phase III trial of sunitinib vs. interferon by Motzer et al. in 2007. In this trial, the improvement in quality of life was modest if compared to the advantage in PFS and response rate, which can be related to the multiple adverse events of sunitinib. Sunitinib-induced toxicity includes fatigue, hypertension, bone marrow toxicity, skin toxicity, and gastrointestinal toxicity. Prevalence of fatigue has been reported to be 92% during administration of chemotherapy agents, while in the case of kidney cancer patients treated with sunitinib, fatigue of any grade has been reported in up to 51-63% of patients, with approximately 7% of them showing grade 3-4 fatigue. According to the definition of NCCN guidelines, cancer-related fatigue is a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. There are a number of general suggestions and behavioral recommendations (e.g. moderate physical activity) that can be easily and effectively implemented in the standard care for treatment and prevention of fatigue in cancer patients. Awareness of these recommendations is still insufficient among physicians. The use of alternative strategies, which include cognitive-behavioral therapies and pharmacological agents may be effective, but present a number of barriers (access to health care workers with appropriate expertise, reimbursement policy, patient's attitude, drug adverse events) that limit their impact in routine clinical practice. The molecular mechanisms of sunitinib-related fatigue are related to off target inhibition of multiple kinases involved in cellular metabolism. In particular, sunitinib inhibits the AMPK enzyme with an IC50 which is in the nanomolar range, thus interfering with catabolic, energy-producing processes, such as glycolysis and lipid oxidation at a systemic level. Furthermore, sunitinib also inhibits GLUT 4-mediated intracellular transport of glucose. For these reasons, sunitinib is likely to cause fatigue via mechanisms which are different with respect to those associated to the underlying cancer and conventional chemotherapy agents. Of note, no randomized, interventional trial has ever been conducted to tackle fatigue in kidney cancer patients treated with sunitinib. The current management of fatigue in these patients remains unsatisfactory at the present time. Quercetin is a naturally occurring flavonol characterized by a phenyl benzo(y)pyrone-derived structure, which belongs to the broader group of polyphenolic flavonoid substances. While quercetin is an aglycone, naturally occurring quercetin compounds are primarily glycosides, with only very small quantity occurring as an aglycone. In particular, isoquercetin is the 3-O- of quercetin. Isoquercetin is hydrolyzed in vivo to form quercetin, which is the reason why the biological effects of quercetin and isoquercetin are pharmacodynamically identical, although isoquercetin is comparatively much more bioavailable than quercetin. Quercetin and isoquercetin are FDA-registered nutritional dietary ingredients suitable for consumption by the general population up to 2 g and 600 mg a day, respectively. For the research purposes of this study, it is noteworthy that quercetin stimulates AMPK in vitro, and it increases GLUT 4 translocation to the cytoplasmic membrane at micromolar concentrations comparable to those possibly achievable with oral administration. These biological effects could positively impact sunitinib-induced fatigue. Quercetin was able to reduce chemotherapy-induced fatigue in mice, while in healthy humans, a randomized, placebo-controlled study showed that supplementation of 500 mg of quercetin twice daily for 7 days provided a statistically significant 13.2% increase in bike-ride time to fatigue.

In conclusion, the following bullet points summarize the background and rationale of this study:

1. sunitinib is the main and most widely used first-line treatment for metastatic kidney cancer and causes fatigue in approximately 50-60% of cases;

2. sunitinib-induced fatigue is likely to be mediated by GLUT-4 and AMPK downregulation;

3. fatigue has a negative impact on quality of life, it increases treatment-related morbidity, it is responsible for treatment delay and interruption, dose reduction and may ultimately reduce sunitinib efficacy;

4. Quercetin is a natural flavonol normally present in food and has been FDA-registered as a nutritional dietary ingredient for the general population up to 1 g per day. Isoquercetin is a quercetin derivative hydrolyzed in vivo to quercetin, and has been considered safe for the general population as a nutritional supplement at a dose of up to 600 mg a day by the FDA. The Institutional Review Board at the Dana-Farber Institution and the FDA have recently approved experimentation of two dose levels of isoquercetin, 500 mg and 1000 mg, to be simultaneously tested in the phase IIb part of a large phase II/III trial for thrombosis prevention in cancer patients (ClinicalTrials.gov: NCT02195232);

5. no significant negative pharmacokinetic /pharmacodynamic interaction during the treatment is expected, as in vivo studies did not show any relevant pharmacokinetic interaction of quercetin with CYP-metabolized drugs;

6. The doses employed in this study are well below the maximum tolerated dose found in a phase I study testing intravenous quercetin (MTD: 1400 mg/m2). In this study, renal toxicity was the main dose limiting toxicity;

7. isoquercetin may reduce fatigue in kidney cancer patients receiving sunitinib on the basis of a molecular rationale, pre-clinical experimental models and clinical data.