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.

Abstract

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.

• Authors: J C Yang, S L Topalian, D J Schwartzentruber, D R Parkinson, F M Marincola, J S Weber, C A Seipp, D E White, S A Rosenberg
• Journal: Cancer (Cancer) Vol. 76 Issue 4 Pg. 687-94 (Aug 15 1995) ISSN: 0008-543X [Print] United States
• PMID: 8625167 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase III, Comparative Study, Journal Article, Randomized Controlled Trial)

Chemical References

• Interleukin-2
• interleukin-2, polyethylene glycol-modified
• Polyethylene Glycols

Topics

• Adult
• Aged
• Carcinoma, Renal Cell (drug therapy)
• Dose-Response Relationship, Drug
• Female
• Humans
• Interleukin-2 (administration & dosage, adverse effects, analogs & derivatives)
• Kidney Neoplasms (drug therapy)
• Male
• Melanoma (drug therapy)
• Middle Aged
• Neoplasm Metastasis
• Polyethylene Glycols
• Prospective Studies