Date: 8/2/2006
Institution: Dana-Farber Cancer Institute
Physician: Irene Ghobrial, MD

This is a phase II study in relapsed/refractory WM patients treated with perifosine. Perifosine has been shown to inhibit and modify signaling through a number of different signal transduction pathways including AKT, MAPK, and JNK. The effects of perifosine on AKT are of particular interest because of 1) the importance of this pathway in the development of most cancers including potentially WM; 2) the evidence that it is often activated in tumors that are resistant to other forms of anticancer therapy; and 3) and the difficulty encountered thus far in the discovery of drugs that inhibit this pathway without causing excessive toxicity.

We have demonstrated significant cytotoxic and anti-proliferative activity of single agent perifosine on WM cell lines and IgM secreting lymphoma cell lines (BCWM1, WSU-WM, MEK1, RL) [data not yet published]. The IC50 of perifosine ranged between 5-20uM indicating strong efficacy at low doses of the agent. In addition, we demonstrated that low doses of perifosine inhibit migration of WM cells indicating that it can potentially inhibit homing and dissemination of WM cells in vivo [data not published]. Based on these studies and its strong preclinical activity in MM and its sparing of normal hematopoetic cells, we hypothesize that perifosine will lead to a significant response rate in a phase II study. It is designed to assess the proportion of overall confirmed responses (CR + PR + MR) using a two-stage phase II study design to permit early stopping of the trial if there is strong evidence that the study regimen is inactive. In addition, it will assess toxicity of this drug in patients with WM. Patients will receive perifosine 150 mg qhs daily. Patients will be assessed by serum immunoelectrophoresis and IgM level at least every 4 weeks.