A Phase I study of granulocyte-macrophage-colony stimulating factor/interleukin-3 fusion protein (PIXY321) following ifosfamide, carboplatin, and etoposide therapy for children with recurrent or refractory solid tumors: A report of the children's cancer group

BACKGROUND. This Phase I trial was developed to determine the safety, biologic activity, and effects on hematopoietic recovery of PIXY321 following ifosfamide, carboplatin, and etoposide chemotherapy for children with recurrent or refractory solid tumors. METHODS. Children (age < 22 years at diagnosis) received ifosfamide 1800 mg/m²/day x 5 days, carboplatin 400 mg/m²/day x 2 days, and etoposide 100 mg/m²/day x 5 days, followed by daily subcutaneous administration of PIXY321. Dose-limiting toxicity was defined as Grade IV toxicity related to PIXY321. Pharmacokinetic and endogenous cytokine production studies were conducted during Course 1, and peripheral blood (PB) progenitor cell and receptor expression studies were conducted during Course 1 when the white blood cell count recovered to ≤1000/mm³. RESULTS. Twenty- four children received ifosfamide, carboplatin, and etoposide chemotherapy plus PIXY321, the latter at doses of 500 μg/m²/day (n = 3), 750 μg/m²/day (n = 6), 1000 μg/m²/day (n = 9), or 500 μg/m²/twice a day (n =6). PIXY321 was well tolerated, with only 1 dose-limiting toxicity (chills, occurring at a dose of 750 μg/m²/day). The maximum tolerated dose was not reached in this study. The median days to absolute neutrophil count recovery (≤1000/mm³) and platelet recovery (>100,000/mm³) during Course 1 following PIXY321 (1000 μg/m²/day) were 22 days (range, 5-33 days) and 20 days (range, 5-31 days), respectively. There was a 2500, 5000, 3000, and 390% increase in PB granulocyte-macrophage colony-forming units, erythrocyte blast-forming units, granulocyte erythrocyte macrophage and megakaryocyte colony-forming units, and CD34+ cells, respectively. CONCLUSIONS. In summary, this pediatric Phase I trial demonstrated that PIXY321 was well tolerated by children and resulted in platelet recovery a median of 20 days after ICE chemotherapy and an increase in the number of PB progenitor cells above baseline. However, based on recent negative results with PIXY321 in randomized Phase II/III trials involving adult subjects, PIXY321 is not currently available for future trials involving children.