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A phase 2 clinical trial of pemetrexed plus gemcitabine as front-line chemotherapy for patients with malignant pleural mesothelioma (MPM).

SOURCE: ASCO, 2004 Annual Meeting

P. A. Janne, C. Obasaju, G. Simon, R. Taub, K. Kelly, P. Fidias, L. P. Bloss, H. L. Kindler; Dana Farber Cancer Institute, Boston, MA; Lilly Oncology, Indianapolis, IN; H. Lee Moffitt Cancer Center, Tampa, FL; Columbia University College, New York, NY; University of Colorado Health Sciences Center, Denver, CO; Massachusetts General Hospital, Boston, MA; University of Chicago Medical Center, Chicago, IL

Background: Pemetrexed and gemcitabine are synergistic in preclinical models. Each agent is active in MPM, but the combination has not been studied in this disease in the phase 2 setting.

Methods: From 12/02 to 06/03, 53 chemo-naive patients with unresectable MPM were enrolled from 12 sites in the US. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8, with pemetrexed 500mg/m2 on day 8, followed by gemcitabine, every 21 days for a total of 6 cycles or until progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis. Pathologic diagnosis included epithelial 68.3%, mixed 12.2%, sarcomatoid 7.3%, and unclassified/other 12.2%. Enrolled patients had a median age of 69.5 years (range: 36 - 88), PS 0:1:2 = 20%:61%:9.8%, and 90% were males.

Results: Toxicity information is currently available on 41 patients. Cycle specific Grade 3/4 hematologic toxicities consisted of neutropenia 33.1%, anemia 1.7%, thrombocytopenia 1.7%, and febrile neutropenia 1.7%. Non-hematologic Grade 3/4 events (% of cycles) were fatigue (5%), neurotoxicity (3.3%), nausea (2.5%), asthenia (1.7%) with the following occurring in < 1% of cycles: vomiting, renal insufficiency, alopecia (grade 1), diarrhea, and rash. Of the 121 cycles administered, 15.7% (n=19) required dose reductions, resulting in a median dose intensity for gemcitabine and pemetrexed of 91.95% and 99.61%. Median number of doses/patient: gemcitabine = 4, pemetrexed = 3. Preliminary response rate=20% out of 34 evaluable patients; CR=0, PR=7 (20%-CI 9-38%), SD=18 (52.9%-CI 35-70%), PD=9 (26.5% CI 13-44%). To date, the clinical benefit rate = 72.9%.

Conclusions: Pemetrexed plus gemcitabine in MPM has an encouraging toxicity profile which is manageable and comparable to other doublet combinations. Especially for the elderly patient with MPM (50% of trial population = 69.5 yrs), this combination of gemcitabine plus pemetrexed may prove a better-tolerated, viable alternative to cisplatin - alimta. Early response data is promising and time-to-event, updated response, and survival information on all 53 patients will be forthcoming.