This is a single-arm phase II trial of perifosine in renal cancer patients who have experienced disease progression after receiving either sorafenib or sunitinib.

This is a single-arm phase II trial assessing the antitumor activity as measured by progression free survival of perifosine in patients with metastatic RCC who have progressed on sorafenib or sunitinib. A total of 48 patients will be enrolled in the trial. All subjects will have histologically confirmed metastatic RCC with predominantly clear cell features (≤ 50% other histologic features). Patients who have been taken off sorafenib or sunitinib may only have been off therapy for less than three months prior to study enrollment. Patients who remain on sorafenib or sunitinib may continue on drug at their current dose until two weeks prior to the initiation of perifosine therapy.

The study consists of three periods: pre-treatment/screening, treatment, and follow-up. Day 1 will be defined as the first day of perifosine therapy. Patients will remain in the treatment phase until progression or toxicity. Patients will be seen by an MD every 3 weeks with 6 weeks defining one cycle of therapy. Tumor evaluations will occur every 6 weeks.

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 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)