PHASE-I TRIAL OF RECOMBINANT INTERLEUKIN-3 BEFORE AND AFTER CARBOPLATIN ETOPOSIDE CHEMOTHERAPY IN PATIENTS WITH SOLID TUMORS - A SOUTHWEST-ONCOLOGY-GROUP STUDY

Recombinant human interleukin 3 (rhIL-3, expressed in Escherichia coli ) is a hematopoietic growth factor with protean biological effects on bone marrow in animal models, including enhanced granulocyte and plate let production and the capacity to ameliorate chemotherapy-induced bon e marrow toxicity. We, therefore, undertook a Phase I trial in patient s with advanced solid tumors and normal bone marrow function. Cohorts of four to six patients each received daily s.c. doses of rhIL-3 (SDZ- ILE-964; Sandoz) at dose levels of 1.0, 2.5, 5.0, and 10.0 mu g/kg acc ording to the following schedule: cycle 1, rhIL-3 days 1-14; cycle 2, carboplatin (350 mg/m(2)) on day 1 and etoposide (100 mg/m(2)) on days 1-3; and cycle 3, carboplatin (350 mg/m(2)) on day 1, etoposide (100 mg/m(2)) on days 1-3, and rhIL-3 on days 4-17. Each cycle was a total of 28 days. An analysis of 20 patients entered into all four escalatin g dose levels revealed that, during cycle 1, absolute neutrophil count (ANC) increased from a median baseline of 6,643/mm(3) to a median of 12,692/mm(3), and platelets increased from a median baseline of 314,00 0/mm(3) to a median of 465,000/mm(3). When cycle 2 was compared with c ycle 3, the median ANC nadir increased from 192/mm(3) to 988/mm(3), an d the mean ANC nadir increased from 458/mm(3) to 1,297/mm(3). Median p latelet count nadirs increased from 29,000/mm(3) to 84,000/mm(3), and the mean nadir platelet counts increased from 72,000/mm(3) to 129,000/ mm(3). Total days on which platelets were <50,000/ mm(3) was 52 for cy cle 2 and 19 for cycle 3. The maximum tolerated dose of rhIL-3 was 5.0 mu g/kg/day; dose-limiting toxicities included fatigue, chills, fever , and headache. These data suggest a clear but variable biological act ivity observed with IL-3, as measured by the reduction in the depth an d duration of thrombocytopenia and/or neutropenia when cycle 2 was com pared with cycle 3. rhIL-3 is a promising cytokine that may help to am eliorate the bone marrow toxicity observed with the use of chemotherap eutic agents.