TY - JOUR
T1 - Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma
T2 - Clinical and immunologic effects
AU - Sosman, J. A.
AU - Weiss, G. R.
AU - Margolin, K. A.
AU - Aronson, F. R.
AU - Sznol, M.
AU - Atkins, M. B.
AU - O'Boyle, K.
AU - Fisher, R. I.
AU - Boldt, D. H.
AU - Doroshow, J.
AU - Ernest, M. L.
AU - Fisher, S. G.
AU - Mier, J.
AU - Vachino, G.
AU - Caliendo, G.
PY - 1993/1/1
Y1 - 1993/1/1
N2 - 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 CD34, CD254 (IL-2 receptor α[IL-2Rα])-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 μg/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 μg/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 1 5) of patients tested at OKT3 dose levels of 200, 400, and 600 μg/m2 had increases in serum sCD25 (soluble IL-2Rα) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-μg 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.
AB - 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 CD34, CD254 (IL-2 receptor α[IL-2Rα])-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 μg/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 μg/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 1 5) of patients tested at OKT3 dose levels of 200, 400, and 600 μg/m2 had increases in serum sCD25 (soluble IL-2Rα) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-μg 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.
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U2 - 10.1200/JCO.1993.11.8.1496
DO - 10.1200/JCO.1993.11.8.1496
M3 - Article
C2 - 8336188
AN - SCOPUS:0027197842
VL - 11
SP - 1496
EP - 1505
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 8
ER -