Phase I trial of etoposide, doxorubicin and cisplatin (EAP) in combination with GM-CSF

The aim of this study was to ameliorate the toxicity of the etoposide, doxorubicin and cisplatin (EAP) regimen and to investigate the feasibility of dose escalation, using the molgramostim form of granulocyte macrophage-colony stimulating factor (GM-CSF) 10 micrograms/kg/day s.c. into the regimen. The design of the trial allowed for amended scheduling of the agents in the event of suboptimal results. Initially the regimen comprised etoposide 120 mg/m2, days 1-3, doxorubicin 40 mg/m2, day 1, and cisplatin 40 mg/m2, days 2 and 8. GM-CSF was begun on day 4 and continued until recovery of granulocyte counts. Courses were repeated every 21 days. 3 patients were treated at these doses. 5 patients received escalated doses (etoposide 180 mg/m2; doxorubicin 60 mg/m2; cisplatin 60 mg/m2) on this schedule; 4 out of 5 had intolerable myelosuppression (grade IV neutropenia or thrombocytopenia lasting > or = 7 days). These results prompted the administration of the day 8 cisplatin dose on day 3, with GM-CSF beginning on day 4. At the lowest doses of each agent (etoposide 120-doxorubicin 40-cisplatin 40), 3 of 6 patients had intolerable myelosuppression, and 3 patients had febrile neutropenia. Dose escalation of all of the drugs to etoposide 180 mg/m2, doxorubicin 60 mg/m2, cisplatin 60 mg/m2 resulted in documented infections in 4 out of 4 patients. GM-CSF toxicity included rash, dyspnoea, arrhythmias and pericardial effusions. The conclusion was that the use of GM-CSF does not permit escalation of drug doses on either schedule of EAP administration, and that these results do not support the combined use of GM-CSF and EAP.