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| |  Temsirolimus Shows Promise in Patients With Relapsed Mantle Cell Lymphoma: Presented at ICML By Chris Berrie LUGANO, SWITZERLAND -- June 17, 2005 -- Temsirolimus, a dihydroester analogue of rapamycin, has substantial antitumour activity in patients with relapsed mantle cell lymphoma (MCL), according to a North Central Cancer Treatment Group phase 2 trial reported here June 11th at the 9th International Conference on Malignant Lymphoma (ICML). Mantle cell lymphoma is a type of B-cell lymphoma that has the characteristic 11, 14 translocation that puts the cyclin D1 gene right next to the heavy chain promoter (on 14q32), and fluorescence in situ hybridisation (FISH) analysis shows the fusion that is diagnostic of mantle cell lymphoma that results in the overexpression of cyclin D1 messenger RNA, explained principal investigator Thomas Witzig, MD, haematologist, Mayo Clinic, Rochester, Minnesota, United States. Dr. Witzig and colleagues conducted a study to determine if temsirolimus, a selective blocker of the cyclin D1 translation regulator mammalian target of rapamycin (mTOR), can produce antitumour responses in patients with MCL. Patient eligibility for this phase 2 trial included biopsy-proven, cyclin D1 - positive MCL that had relapsed or was refractory to therapy. This included measurable disease, a performance status (PS) of Eastern Cooperative Oncology Group 0-2), and adequate organ and marrow function (platelet count >75,000). Patients received a dose of 250 mg temsirolimus in a 30-minute IV infusion on days 1, 8, 15, and 22, for a cycle of 28 days. The primary end point was tumour response, with at least a 20% response rate. Patients were assessed after cycles 1, 3, and 6. No response after cycle 6 resulted in removal from the study. Complete remission (CR) received a further 2 cycles; partial remission (PR) continued for up to 12 cycles. For the full 250 mg temsirolimus dose, a neutrophil count above 1,000 and a platelet count above 50,000 was necessary before each dose. There were dose modifications built into the study, as necessary. The 34 eligible patients showed typical characteristics of relapsed MCL -- median age of 70 years (range, 38-88 years); 91% had stage IV disease; 69% had 2 or more extrandal sites involved; 54% were refractory to last treatment; median of 3 prior treatments (range, 1-11). Previous treatments included rituximab in 89%; alkylator in 94%; anthracyclin in 83%; purine neucleoside analogue in 57%; platinum analogue in 29%; and transplantation in 11%. The overall response rate was 38%, with 1 complete response and 12 partial responses. The median time to response was 1 month. "These responses tended to occur very rapidly, with 8 of the 13 responses occurring at the first response-assessment time, which was after 1 cycle," Dr. Witzig said. For the total cycles received, the single patient who had a complete response received 6 cycles, as planned, while 3 of the patients who had partial responses received 12 cycles per protocol. The remaining 9 partial responses received a median of 6.5 cycles (range, 3-10), with 8 going off study prior to completion of the full planned 12 cycles (tumour progression in 3 patients, adverse events in 3, and refusal in 2). The remaining 22 nonresponders comprised 14 who progressed without response, and 7 who went off study (adverse events in 4, refusal in 1, alternative treatment in 1, and other medical problems in 1). Time to progression was: median 6.5 months (range, 2.9-8.3 months) and median duration of response was 6.9 months (range, 5.2-12.4 months). Toxicity was mainly haematological and occurred in 63% of patients who had grade 3 events due to low platelet counts. The nonhaematological toxicity was particularly mild, with no infusion-related adverse events. Overall, 74% of the patients had grade 3 toxicity of some type, and 17% had grade 4. Toxicities resulted in dose reductions in 89% on the 250 mg dose. This resulted in a median temsirolimus monthly dose of 525 mg (131 mg/week). There was no difference between responders and nonresponders for a total dose/month (554 vs. 525, respectively). For the pharmacodynamics, the mTOR activity in blood from a limited number of these patients indicated no direct correlation between tumour response and mTOR activity, although this aspect requires further investigation, Dr. Witzig said. "As the toxicity for 250 mg was substantial from a haematological point of view, and since we wanted to combine this with other drugs, we essentially went on to do the study over again using a lower dose of 25 mg," he explained. Although ongoing, this further study indicates a much-reduced incidence of grade 3 thrombocytopaenia, with little or no reduction in overall response rate with this much-reduced dose of temsirolimus. The aim of future research will be to combine low-dose temsirolimus with rituximab immunotherapy. Reference:
[Study title: Final Results of a Phase 2 Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma. Abstract 095]
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