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

Inclusion Criteria:

1. Patients must have received no prior systemic therapy other than sunitinib (including interleukin-2, interferon-α, chemotherapy, bevacizumab, mTOR inhibitor sorafenib or other VEGF TKI) for advanced or metastatic RCC. Patients who received adjuvant treatment with a cancer vaccine are eligible.
2. Patients with locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma of any histology (equivalent to Stage IV RCC according to AJCC staging) for whom treatment with sunitinib is either planned or ongoing. Patients with non-measurable disease are allowed if metastatic disease can be confirmed;
3. Patients for whom treatment with sunitinib is planned must have had a whole body CT scan within 30 days prior to enrollment; patients who are already being treated with sunitinib at the time of enrollment must have had a whole body CT scan showing non progressive disease according to the RECIST criteria within 30 days of enrollment;
4. ECOG PS of 0 or 1;
5. Age ≥18 years;
6. A female is eligible to enter and participate in this study if she is non-childbearing potential or agrees to use adequate contraception;
7. Adequate organ system functions;
8. Total serum calcium concentration \<12.0mg/dL;
9. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as assessed by echocardiography (ECHO) or multigated acquisition (MUGA) scan. The same modality used at baseline must be applied for subsequent evaluations;
10. Patient is able to swallow and retain oral tablets;
11. Written informed consent obtained before any screening procedure and according to local guidelines.

Exclusion Criteria:

1. History of another malignancy;
2. History or clinical evidence of central nervous system (CNS) metastases
3. Any clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding or affect absorption of investigational product
4. Unable to tolerate continuous daily administration of 50 mg sunitinib
5. Presence of uncontrolled infection;
6. Serum potassium \< lower normal limits;
7. Corrected QT interval (QTc) \>480 ms using Bazett's formula;
8. History of cardiovascular conditions within the past 6 months:
9. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of \> 150mmHg or diastolic blood pressure (DBP) of \> 90mmHg) at baseline
10. History of cerebrovascular accident (CVA) including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months;
11. Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major).
12. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels;
13. Evidence of active bleeding or bleeding diathesis;
14. Significant hemoptysis within 6 weeks prior to first dose of study drug;
15. Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with patient's safety, obtaining informed consent or compliance to the study;
16. Use any prohibited medications within 14 days of the first dose of study medication;
17. Use of an investigational agent, including an investigational anti-cancer agent, within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study drug;
18. Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of study treatment;
19. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to or sunitinib;
20. Pregnant or lactating female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug;
21. Clinically significant depression (PHQ-9 score \>15), anxiety (GAD score \>10), clinically significant insomnia (positivity of ISQ).