Safety and biological activity of repeated doses of recombinant human Flt3 ligand in patients with bone scan-negative hormone-refractory prostate cancer.

PURPOSE: The purpose of this study was to evaluate the safety, biological activity, and feasibility of repeated doses of the dendritic cell (DC)-stimulating agent Flt3 ligand (FL) in patients with bone scan-negative hormone-refractory prostate cancer. EXPERIMENTAL DESIGN: Thirty-one patients with hormone-refractory prostate cancer who had elevated prostate-specific antigen (PSA) levels and negative bone scans were enrolled. Six cycles (28 days each) were planned. In the first cycle, patients were randomized to FL or placebo. All patients received open-label FL during the next five courses. DC, anti-FL antibody, and PSA levels were measured every 15 days to assess biological activity. RESULTS: DCs increased markedly in FL-treated patients from precycle to day 15, and the increase was consistent in each cycle. Mean percentages of DCs in peripheral blood ranged from 1.4% to 1.9% precycle and from 10.1% to 13.9% on day 15, and after the first cycle, absolute counts on day 15 were approximately 29-fold higher than precycle levels. Natural killer cell counts (CD56(+)) were found to be elevated after cycle 1 (154% increase versus 2.8% decrease in placebo group at day 22). Twenty-two of 27 patients tested developed nonneutralizing anti-FL antibody. The most frequently experienced toxicity was injection site reaction, followed by asthenia, rash, and diarrhea. Although median PSA levels did not vary during any cycle, a significant slowing in velocity of PSA was observed while patients were on-study (relative velocity = 0.002) compared with prestudy PSA velocity (relative velocity = 0.007). CONCLUSIONS: FL was well tolerated. FL consistently produced an increase in DC count without any evidence of decreasing response with continued exposure. The expansion of DCs and the slowing of PSA velocity after administration of FL suggest potential clinical applications in the immunotherapy of prostate cancer.

Etanercept added to background methotrexate therapy in patients with rheumatoid arthritis: continued observations.

OBJECTIVE: To observe the long-term safety and efficacy of combination therapy with etanercept and methotrexate in patients with rheumatoid arthritis (RA), and to determine whether the addition of etanercept allowed reductions in methotrexate or corticosteroid dosages while maintaining a clinical response. METHODS: Patients with RA who received methotrexate plus etanercept in a previous randomized, placebo-controlled trial were offered the opportunity to enroll in an open-label extension study for further evaluation of treatment with etanercept and methotrexate. RESULTS: Seventy-nine of the 89 patients in the original blinded study enrolled in the extension study, and 65 of these patients continue in the study. Patients have received etanercept therapy for up to 47 months (median 44 months). The types and rate of adverse events noted during the extension trial were similar to those observed in the controlled trial. At the 3-year assessment, 77% of the 57 patients available for evaluation met American College of Rheumatology 20% (ACR20) criteria for improvement in RA, 47% met the ACR50 criteria, and 23% met the ACR70 criteria. Of the 36 patients assessed at 3 years in the extension study, 30 (83%) were able to decrease their dosages of corticosteroids, and 20 (56%) were able to discontinue corticosteroid therapy. At 3 years, the dosage of methotrexate was decreased in 41 of 66 patients (62%), and methotrexate therapy was discontinued in 19 patients (29%). CONCLUSION: In this observational continuation study, the addition of etanercept to background methotrexate provided sustained clinical benefit over a median period of 44 months. With etanercept therapy, there were trends toward dosage reduction or discontinuation of methotrexate and corticosteroids, without apparent worsening of ACR response rates. Compared with the controlled trial, no increases in the rate of adverse events were observed.