Date: 5/18/2003
Sponsor: Celgene Corp.
Institution: Dana-Farber Cancer Institute and affiliated WMCTG sites in USA
Physician: Dr. Steven Treon

In an effort to extend the activity of rituximab using immunomodulators instead of chemotherapy, DFCI 03-077, a phase II study is examining the activity of combined Thalidomide and Rituximab in Thalidomide and Rituximab naïve WM patients who are symptomatic and in need of treatment. Thalidomide as a single agent, and in combination with steroids has been extensively evaluated in the treatment of plasma cell malignancies, including Waldenstrom's macroglobulinemia. The precise mechanism(s) by which thalidomide exerts its anti-tumor effects among the plasma cell malignancies remains to be established, however its role as an immunomodulator has been suggested in studies by us and others to enhance T-cell proliferation, natural killer cell expansion, and tumor cell killing by thalidomide treated natural killer cells. Recently, as discussed above, we demonstrated that Thalidomide and its analogue Revimid significantly enhanced Rituximab mediated ADCC activity of peripheral blood mononuclear cells. The combination of Thalidomide and Rituximab has been evaluated in patients with CHOP relapsed or refractory Mantle Cell Lymphoma (MCL) by Drach et al. Patients in this study received 4 weekly infusions of Rituximab (375 mg/m2), along with Thalidomide 200 mg po qD which was increased to 400 mg po qD, and continued until disease progression. Ten out of 11 (90%) of the MCL patients who received this combination responded (3 CR, 7 PR), which favorably compared to studies in which MCL patients received Rituximab alone, in whom an ORR of 30% has previously been reported. As part of the study objectives, we will be seeking to 1) to define objective response (ORR, CR, PR, MR), time to treatment failure, and toxicity for combined Thalidomide and Rituximab therapy in Waldenstrom's macroglobulinemia patients; and 2) we will also be seeking to define the mechanism(s) of action for combined Thalidomide and Rituximab activity by performing extensive corollary studies.