PHASE-I TRIAL OF SUBCUTANEOUS INTERLEUKIN-3 IN PATIENTS WITH REFRACTORY MALIGNANCY - HEMATOLOGICAL, IMMUNOLOGICAL, AND PHARMACODYNAMIC FINDINGS

We conducted a Phase I trial of s.c. recombinant human interleukin 3 ( rhIL-3) to evaluate the toxicity, maximal tolerated dose, pharmacokine tics, and in vivo biological effects of this cytokine. Thirty-one pati ents with refractory cancer were entered into the study between Novemb er 1991 and June 1993. Therapy consisted of s.c. rhIL-3 daily for 15 d ays administered to cohorts of three to nine patients at dose levels o f 60-4000 mu g/m(2)/day. Cycles were repeated at intervals of 28 days. Seventy-five cycles of rhIL-3 were administered (median, two per pati ent) and the maximal tolerated dose was 2000 mu g/m(2)/day. Toxicity w as moderate, with most patients developing chills, fever, and myalgia, Dose-limiting toxicity consisted of diarrhea (two patients) and heada che (one patient). Hematological effects of rhIL-3 included significan t dose-related increases of WBC (P < 0.001), neutrophils (P < 0.001), and eosinophils (P < 0.001). Platelet counts and absolute lymphocyte n umbers also increased, Various CD3(+) lymphocyte subsets increased; ho wever, lytic activity (natural killer and lymphokine-activated killer) of peripheral blood lymphocytes was not enhanced, Serum levels of the soluble IL-2 receptor increased in a dose-related fashion, and IL-2-i nduced lymphocyte proliferation also was increased variably, Pharmacok inetic studies were performed in 13 patients, and area under the curve and maximal concentration values increased with increasing rhIL-3 dos e levels (P < 0.001) and correlated with maximal changes from baseline in WBC, neutrophils, and eosinophils. rhIL-3 antibodies were detected in 8% of patients by day 29 of cycle 1 but were not neutralizing. rhI L-3 is well tolerated when administered s.c. and has reproducible hema tological and immunological effects. The pleiotropic effects of this c ytokine on various in vivo biological parameters were demonstrated cle arly, Further studies of its immunoregulatory effects are warranted.