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.