Study of Propranolol Plus Sunitinib in First-line Treatment of Metastatic Renal Cell Carcinoma

Inclusion Criteria:

Patients are eligible to be included in the study only if they meet all of the following criteria:

1. Histological diagnosis of clear-cell renal cell carcinoma (RCC) or mixed-type RCC with more than 60% of clear-cell component.
2. Diagnosis of stage IV RCC (primary metastatic or recurrence after surgical procedure).
3. Prior nephrectomy (complete or partial).
4. Presence of measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1.
5. Karnofsky performance status score of 80-100%.
6. Favourable- or intermediate-risk according to Memorial Sloan Kettering Cancer Center criteria.
7. Adequate organ function, including the following:

   1. hepatic: total bilirubin ≤ 2 times the upper limit of normal (excluding patients with Gilbert syndrome), aspartate aminotransferase and alanine aminotransferase ≤ 5 times the upper limit of normal,
   2. renal: serum creatinine ≤ 2 times the upper limit of normal,
   3. bone marrow: absolute neutrophil count ≥ 1500/mm3, platelets ≥ 100000/mm3, hemoglobin ≥ 9.5 g/dl.
8. Normal thyroid function (natural or with supplementation of thyroid hormones) defined as thyroid-stimulating hormone within limits of normal.
9. Age eighteen years or older on the day of consent.
10. Written informed consent prior to study entry.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Prior systemic pharmacotherapy of RCC.
2. Treatment with propranolol within 6 months of study entry.
3. Metastases in central nervous system (patients who had central nervous system metastases that were surgically resected and/or treated with radiotherapy in the past and now are without neurological symptoms, are allowed on protocol).
4. Female patients who are pregnant or breast feeding or adults of reproductive potential who are not using effective birth control methods.
5. Presence of other malignancies (patients with carcinoma in situ of the cervix or basal cell carcinoma of the skin are allowed on protocol).
6. Presence of any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

   1. heart failure of New York Heart Association Class III or IV, significant cardiac arrhythmia or any other clinically significant cardiovascular disease,
   2. unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of entering the study,
   3. severely impaired respiration as defined as O2 saturation that is ≤ 90% at rest on room air,
   4. uncontrolled diabetes as defined by fasting serum glucose \> 1.5 times the upper limit of normal,
   5. ejection fraction less than 40% (measured at echocardiography),
   6. significant liver disease such as cirrhosis, active hepatitis or chronic persistent hepatitis,
   7. active (acute or chronic) infections requiring antimicrobial intervention.
7. Concomitant treatment with:

   1. chronic, systemic corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed,
   2. strong CYP3A4 inducers/inhibitors: carbamazepine, phenytoin, rifabutin, rifampin, nafcillin, phenobarbital, St John's wort, itraconazole, ketoconazole, erythromycin, clarithromycin, nefazodone.
8. Known allergy/sensitivity to sunitinib and/or propranolol.
9. Galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
10. Immunization with attenuated live vaccines within 30 days of study entry.
11. Human immunodeficiency virus sero-positivity at the study entry or in the past.
12. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib and/or propranolol (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
13. Presence of active, bleeding diathesis.
14. Major surgery (defined as requiring general anesthesia) and/or significant traumatic injury (requiring \> 28 days to heal) within 28 days of the study entry; presence of side effects due to any surgery or probable requirement of major surgery during the course of the study.
15. Present contraindications to propranolol, that include: bronchial asthma, prolonged fasting, acidosis, hypotension (systolic blood pressure less than 90 mmHg, diastolic blood pressure less than 60 mmHg), severe peripheral arterial circulatory disturbance, cardiogenic shock, bradycardia, Prinzmetal's angina, uncontrolled heart failure, second or third degree heart block, untreated phaeochromocytoma, sick sinus syndrome.
16. Inability or unwillingness of subject or legal guardian/representative to give written informed consent.