The use of polyethylene glycol-modified interleukin-2 (PEG- IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG- IL-2.
BACKGROUND. Conjugation of polyethylene glycol to recombinant human interleukin-2 ( IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG- IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life. In mice, one dose of PEG- IL-2 results in tumor regression comparable to that achieved with multiple bolus doses of IL-2. Based on these preclinical studies, a Phase I study with PEG- IL-2 was undertaken in patients with metastatic renal cell carcinoma (RCC) and melanoma. Then, to exploit the higher peak levels attained with IL-2 and the improved trough levels of PEG- IL-2, a combination regimen beginning with bolus IL-2 followed by low dose maintenance PEG- IL-2 was devised and tested for efficacy. METHODS. Patients with measurable metastatic melanoma or RCC were entered in a Phase I dose escalation trial of PEG- IL-2 given once a week by intravenous bolus. This trial then was repeated using a twice-a-week schedule. After determining the maximum tolerated dose (MTD) and a safe outpatient regimen for PEG- IL-2, a hybrid regimen combining an initial high dose IL-2 cycle followed by chronic maintenance with weekly PEG- IL-2 was devised. This regimen was compared with a standard regimen consisting of two cycles of high dose unconjugated IL-2 in a randomized prospective clinical trial. RESULTS. When given by intravenous bolus once a week, the MTD of PEG- IL-2 was 12 million IU/m2, with toxicities similar to those of unconjugated IL-2. A twice-a-week schedule was less well tolerated. Of 28 patients given 32 treatment courses at varied dose levels, there were two partial responses and one minor response. A total of 124 patients with metastatic melanoma or RCC were randomized to either standard unconjugated IL-2 therapy or the hybrid regimen. There was no treatment-related mortality in either arm, and the use of PEG- IL-2 resulted in a significant decrease in the need for intensive-care-unit care. The response rates (partial response and complete response) for patients with RCC and melanoma were 19% and 15%, respectively, for IL-2 alone and 17% and 11%, respectively, for the IL-2 and PEG- IL-2 combination. CONCLUSIONS. The combination of high dose IL-2 followed by PEG- IL-2 is a well tolerated regimen with significant activity against RCC and melanoma, but it shows no significant increase in antitumor activity compared with high dose IL-2 alone.[1]References
- The use of polyethylene glycol-modified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2. Yang, J.C., Topalian, S.L., Schwartzentruber, D.J., Parkinson, D.R., Marincola, F.M., Weber, J.S., Seipp, C.A., White, D.E., Rosenberg, S.A. Cancer (1995) [Pubmed]
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