A phase I study of the GM-CSF antagonist E21R

Purpose: E21R is a competitive inhibitor of GM-CSF. This is the initial clinical study to investigate the safety, toxicity and pharmacokinetics of escalating doses of E21R. Patients and methods: Cohorts of three patients received doses of 10, 30, 100, 300, 600 and 1000 μg/kg per day given subcutaneously daily for 10 days. Eligible patients had solid tumours known to express GM-CSF receptors (breast, prostate, colon and lung cancer, and melanoma). No bone marrow involvement or concomitant steroids were permitted. A total of 22 patients received doses ranging from 10 to 1000 μg/kg per day. There were 18 males and 4 females with a median age of 60 years (range 33 to 81 years). Eight patients had an ECOG performance status of 0, seven a performance status of 1, and seven a performance status of 2. There were ten patients with colon cancer, four with prostate cancer, three with lung cancer, three with melanoma and two with breast cancer. Results: E21R was in general well tolerated and the maximum tolerated dose was not reached. The most severe toxicities were WHO grade 3 injection site erythema in one patient and grade 2 in two patients, grade 2 lethargy in three patients and grade 2 muscle aches and soreness, grade 2 joint pains and grade 2 thirst in one patient each. The primary pharmacokinetic parameters were dose-independent. Dose-dependent transient eosinophilia was noted from day 3. A fall in PSA levels was recorded in two patients with prostate cancer during their initial cycles of E21R, but they subsequently rose again. Serum from patients treated at 600 and 1000 μg/kg per day antagonized GM-CSF-mediated TF-1 cell proliferation in vitro. Conclusion: E21R can be safely given at doses up to 1000 μg/kg per day.