A phase II trial of perifosine in patients with advanced renal cell carcinoma (RCC) who have failed tyrosine kinase inhibitors (TKI)

5101 Background: The recently demonstrated activity of inhibitors of TORC1 in RCC has raised the possibility that even greater effects may be achieved by targeting upstream of this pathway. Perifosine is a synthetic alkylphospholipid which inhibits Akt activity and also has cell-dependent effects upon the MAP-kinase pathway. Prior single-agent trials showed disease stabilization/regression in patients (pts) with advanced RCC; however, few pts were previously treated with a TKI. Therefore, we conducted a multi-center phase II trial to determine the safety and efficacy of perifosine in pts with advanced RCC refractory to VEGFR TKI. Methods: Primary objectives were to measure the % of pts progression-free at 12 weeks (wks) and overall progression-free survival (PFS) of perifosine (100 mg qhs). Secondary objectives included overall response rate (> PR), and safety, Eligibility: ECOG PS 0–1, pts with metastatic RCC who have RECIST defined progression on either sunitinib or sorafenib. Prior Rx with immunotherapy and bevacizumab was permitted. Normal organ and marrow function required. Results: From 4/07–10/08, 24 pts were treated at four sites. Median age 67 (range 47–78) and 16 were male; 90% of pts had predominantly clear cell histology. Prior sunitinib = 12; prior sorafenib = 12 (1.5 avg prior Rx). As of 12/08, all 24 pts were evaluable for PFS, response and toxicity as follows in the table . 6/24 pts remain on treatment (range 7 - 84 wks). Therapy was well tolerated with primarily Grade (G) 1 & 2 adverse events. G 3 & 4 events were: dyspnea (8%), hyponatremia (8%), pulmonary embolism (4%) and arthalgia (4%). Conclusions: Perifosine has promising activity in pts with RCC who have failed prior TKI therapy. The favorable toxicity profile suggests potential for combinational therapies with VEGF-targeted agents. Additional studies are under consideration to evaluate perifosine for clinical benefit in pts with previously treated RCC. [Table: see text] [Table: see text]