Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study

Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.