Inclusion Criteria:

• Patients will be required to have clear cell renal cell carcinoma with less than 50% of any other histology (papillary or chromophobe or oncocytic). There must be histologic confirmation by the treating center of either the primary or a metastatic lesion
• Patients must have experienced disease progression by RECIST criteria while on sorafenib or sunitinib
• Patients must be off of sorafenib or sunitinib for >= 2 weeks prior to initiation of perifosine and <= 3 months prior to enrollment
• Patients may have had sorafenib or sunitinib in the adjuvant setting as long as they have experienced disease recurrence while on therapy
• Patients must have measurable disease that is not curable by standard radiation therapy or surgery
• Age >= 18 years
• ECOG performance status 0 or 1

• Patients must have the following laboratory values

  • Hgb> 9.0gm/dl (transfusions allowed prior to enrollment)
  • WBC Blood Count (WBC) >= 3,000/mm3
  • Absolute Granulocyte Count (AGC) >= 1,200/mm3
  • Platelet Count >= 100,000/mm3
  • Serum creatinine <= 2.0 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) > 40ml/min (neither drug is cleared by the kidney)
  • CrCl= Wt (kg) x (140-age)*/72 x Cr. level, *female x 0.85)
  • Total Bilirubin < 1.5 x ULN
  • AST/ALT <= 2.5 x ULN (or <= 5.0 x ULN in the presence of liver metastasis)
  • INR <= 1.5 and aPTT within normal limits if not on anticoagulant therapy
  • fasting serum cholesterol < 350 mg/dL (9.0 mmol/L)
  • fasting serum triglycerides < 400 mg/dL (4.56 mmol/L)
• Life expectancy greater than 6 months
• No prior malignancy diagnosed within the past 3 years. Any prior malignancy must have a very likely cure rate
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method birth control or abstinence) prior to study entry for the duration of study participation and for 4 weeks after the last dose of study medication. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
• Patients must have the ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• History or clinical evidence of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastasis, or history of stroke
• Other than sorafenib or sunitinib, patients may have only had prior immunotherapy for stage IV disease
• Patients may have had prior sorafenib OR sunitinib and cannot have been treated with both TKIs
• Patients who have stopped sorafenib or sunitinib due to toxicity but have only progressed off therapy will not be allowed
• Patients may have had prior anti-angiogenic such as bevacizumab only if given in combination with either sorafenib or sunitinib
• Prior Thalidomide or IFNα are allowed for adjuvant therapy or stage IV disease
• Patients may not have had prior mTOR inhibitors (CCI-779, RAD001)
• History of bleeding diathesis or coagulopathy
• A condition that impair patient's ability to swallow pills

• Patients with clinically significant cardiovascular disease

  • Myocardial infarction or unstable angina < 6 months prior to registration
  • New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
  • Grade II or greater peripheral vascular disease
• No serious non-healing wound, ulcer or bone fracture
• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parental antibiotics on day 0, clinically significant cardiovascular disease, New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 1 year prior to study entry, or psychiatric illness/social situations that would limit compliance with study requirements
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with perifosine
• Tissue block containing tumor tissue must be submitted all patients pre-treatment as a requirement for enrollment on the protocol. In the event that tissue blocks are not available, ten unstained paraffin-embedded slides containing tumor tissue will be requested