Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects.

Abstract

PURPOSE:

To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2.

PATIENTS AND METHODS:

We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2.

RESULTS:

A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response).

CONCLUSION:

The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.

• Authors: J A Sosman, G R Weiss, K A Margolin, F R Aronson, M Sznol, M B Atkins, K O'Boyle, R I Fisher, D H Boldt, J Doroshow
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 11 Issue 8 Pg. 1496-505 (Aug 1993) ISSN: 0732-183X [Print] United States
• PMID: 8336188 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Interleukin-2
• Muromonab-CD3
• Receptors, Interleukin-2

Topics

• Adult
• Aged
• Carcinoma, Renal Cell (immunology, secondary, therapy)
• Female
• Humans
• Injections, Intravenous
• Interleukin-2 (administration & dosage, therapeutic use)
• Leukocyte Count
• Male
• Melanoma (immunology, secondary, therapy)
• Middle Aged
• Muromonab-CD3 (therapeutic use)
• Receptors, Interleukin-2 (metabolism)
• T-Lymphocytes