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 CHILDRENS CANCER GROUP

BACKGROUND. This Phase I trial was developed to determine the safety, biologic activity, and effects on hematopoietic recovery of PIXY321 fo llowing ifosfamide, carboplatin, and etoposide chemotherapy for childr en with recurrent or refractory solid tumors. METHODS. Children (age < 22 years at diagnosis) received ifosfamide 1800 mg/m(2)/day x 5 days, carboplatin 400 mg/m(2)/day x 2 days, and etoposide 100 mg/m(2)/day x 5 days, followed by daily subcutaneous administration of PIXY321. Dos e-Limiting toxicity was defined as Grade IV toxicity related to PIXY32 1. Pharmacokinetic and endogenous cytokine production studies were con ducted during Course 1, and peripheral blood (PB) progenitor cell and receptor expression studies were conducted during Course 1 when the wh ite blood cell count recovered to greater than or equal to 1000/mm(3). RESULTS. Twenty-four children received ifosfamide, carboplatin, and e toposide chemotherapy plus PIXY321, the latter at doses of 500 mu g/m( 2)/day (n = 3), 750 mu g/m(2)/day (n = 6), 1000 mu g/m(2)/day (n = 9), or 500 mu g/m(2)/twice a day (n = 6). PIXY321 was well tolerated, wit h only 1 dose-limiting toxicity (chills, occurring at a dose of 750 mu g/m(2)/day). The maximum tolerated dose was not reached in this study . The median days to absolute neutrophil count recovery (greater than or equal to 1000/mm(3)) and platelet recovery (>100,000/mm(3)) during Course 1 following PIXY321 (1000 mu g/m(2)/day) were 22 days (range, 5 -33 days) and 20 days (range, 5-31 days), respectively. There was a 25 00, 5000, 3000, and 390% increase in PB granulocyte-mac rophage colony -forming units, erythrocyte blast-forming units, granulocyte erythrocy te macrophage and megakaryocyte colony-forming units, and CD34+ cells, respectively. CONCLUSIONS. In summary, this pediatric Phase I trial d emonstrated that PIXY321 was well tolerated by children and resulted i n 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 availabl e for future trials involving children. Cancer 1998;83:1449-60. (C) 19 98 American Cancer Society.