Evaluate Safety and Tolerability in Dose Escalation of Sorafenib in Advanced Renal Cell Cancer

A Phase II Study of the Efficacy and Tolerability of the Dose Escalation of Sorafenib in Advanced Renal Cell Cancer

The purpose of this study is to determine whether an increase in the dose of sorafenib when given over five instead of 7 days/week, will result in an improvement of the response rate (degree of shrinkage of your cancer) and an improvement in the length of time that sorafenib will control your cancer, without causing a significant increase in side effects.

In 2006, an estimated 38,890 people in the United States were diagnosed with kidney cancer and greater than 12,000 died from the disease. Kidney cancer that has spread to other parts of the body is one of the most treatment-resistant diseases. Standard of care treatment usually involves chemotherapy. Results from chemotherapy have been disappointing. Therefore, there is a need to develop additional safe and effective therapies to treat advanced kidney cancer.

Sorafenib (Nexavar®) has been approved by the FDA for the treatment of advanced kidney cancer. Sorafenib works by interfering with a type of protein in your body that determines how your kidney cells work and grow. Sorafenib at standard doses for 400mg(two pills) twice/day, given seven days/week, may slow progression of the disease for an average of three months but it is not expected to be curative. Preliminary studies have suggested higher doses of sorafenib may increase the chance that the tumor will shrink.

Inclusion Criteria

• Age ≥ 18 years old.

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

• Adequate bone marrow, liver and renal function as assessed by the following:

  • Hemoglobin ≥ 9.0 grams per deciliter (g/dl)
  • Absolute neutrophil count (ANC)≥ 1,500/mm3
  • Platelet count ≥ 100,000/mm3
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • and aspartate aminotransferase (AST) ≤ 2.5 times the ULN (≤ 5 x ULN for patients with liver involvement)
  • Creatinine < 1.5 times ULN

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to of treatment.

• Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study. Men should use adequate birth control for at least three months after the last administration of sorafenib.

• Ability to understand and willing to sign written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

• International normalized ratio (INR) < 1.5 or a prothrombin time/partial prothrombin time (PT/PTT) within normal limits unless receiving anti-coagulation treatment with an agent such as warfarin or heparin. These patients may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

• Must have histologically or cytologically confirmed renal cell carcinoma that is metastatic (M1). Patients with unresectable primary tumor (but MO) are also eligible.

• Must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension. Soft tissue disease that has been radiated in the 2 months prior to registration is not assessable as measurable disease. Soft tissue disease within a prior radiation field must have progressed to be considered assessable. X-rays, scans or physical examinations used for tumor measurement must have been completed within 28 days prior to registration. X-rays, scans or physical examinations for non-measurable disease must have been completed within 42 days prior to registration.

• Patients with metastatic disease who have a resectable primary tumor and are deemed a surgical candidate may have undergone resection and have recovered from surgery. At least 28 days must have elapsed since surgery and must have recovered from any adverse effects of surgery.

• May have received 1 prior immunotherapy with either interferon (IFN) and/or Interleukin-2 (IL-2) or the combination of IFN/IL2 and only 1 prior biologic agent (sunitinib, bevacizumab, or temsorlimus). Must have progressed during this prior therapy. At least 14 days must have elapsed since the last treatment and must have recovered from any adverse effects of prior therapy. May have received prior radiation therapy. At least 21 days must have elapsed since completion of prior radiation therapy. Must have recovered from all associated toxicities at the time of registration.

Exclusion Criteria

• Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within past 6 months.
• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
• Patients who have received prior sorafenib are ineligible.
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B/C.
• Active clinically serious infection > CTCAE Grade 2.
• Thrombosis or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. Patients with renal or caval thrombosis related to the primary renal tumor would not be excluded and are eligible.
• Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose of study drug.
• Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose of study drug.
• Serious non-healing wound, ulcer, or bone fracture.
• Evidence or history of bleeding diathesis or coagulopathy.
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.
• Use of St. John's Wort or rifampin (rifampicin).
• Known or suspected allergy to sorafenib or any agent given in the course of this trial.
• Any condition that impairs patient's ability to swallow whole pills.
• Any malabsorption problem.