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 platelet production and the capacity to ameliorate chemotherapy-induced bone marrow toxicity. We, therefore, undertook a Phase I trial in patients 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 μg/kg according to the following schedule: cycle 1, rhIL-3 days 1–14; cycle 2, carboplatin (350 mg/m²) on day 1 and etoposide (100 mg/m²) on days 1–3; and cycle 3, carboplatin (350 mg/m²) on day 1, etoposide (100 mg/m²) 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 escalating dose levels revealed that, during cycle 1, absolute neutrophil count (ANC) increased from a median baseline of 6, 643/mm³ to a median of 12, 692/mm³, and platelets increased from a median baseline of 314, 000/mm3 to a median of 465, 000/mm³. When cycle 2 was compared with cycle 3, the median ANC nadir increased from 192/mm³ to 988/mm³, and the mean ANC nadir increased from 458/mm³ to 1, 297/mm³. Median platelet count nadirs increased from 29, 000/mm³ to 84, 000/mm³, and the mean nadir platelet counts increased from 72, 000/mm³ to 129, 000/mm³. Total days on which platelets were <50, 000/mm³ was 52 for cycle 2 and 19 for cycle 3. The maximum tolerated dose of rhIL-3 was 5.0 μg/kg/day; dose-limiting toxicities included fatigue, chills, fever, and headache. These data suggest a clear but variable biological activity observed with IL-3, as measured by the reduction in the depth and duration of thrombocytopenia and/or neutropenia when cycle 2 was compared with cycle 3. rhIL-3 is a promising cytokine that may help to ameliorate the bone marrow toxicity observed with the use of chemotherapeutic agents.