Phase Ib clinical trial and pharmacokinetic evaluation of recombinant human granulocyte-macrophage colony stimulating factor(rh GM-CSF LBD-005) in advanced cancer patients with chemotherapy induced myelosuppression

Abstract

To define the clinical safeties and hematologic effects of subcutaneously administered yeast- derived recombinant human granulocyte-macrophage colony stimulatina factor(rh GM-CSF, LBD-005h and to determine the maximally tolerated dose(MTD) and the pharmacokinetics. Sngle arm open non-randomized phase Ib study was carried in 15 cancer patients#(14 patients evaluable) with chemotherapy induced bone marrow depression. Rh GM-CSF by once-daily subcutaneous administration to groups of 3-6 patients at doses of 50, 100, 150, 250, 350, 500, 700 ug/m/d for 10 consecutive days was escalated unless greater than WHO grade III toxicites were observed. Intrapatient dose escalation was permitted. Clinical safeties and toxicities were observed with frequent hematologic monitering. Blood and urine were collected on day 1, and 8 of rh GM-CSF administration to evaluate the parmacokinetic parameters. Of the 15 enrolled patients, 14 patients were evaluable. Male to female ratio was 8: 6 with median age 32 y-o(10~70 y-o). Seven patients had osteosarcoma, 2 malignant lymphoma, 2 gastric carcinoma, 2 lung cancer and 1 had uterine leiomyosarcoma. The total administered cycles of rh GM-CSF were 24. At each dose step, 3 patients were treated with exception of 6 patients at 500 ug/m/d dose. At all the doses administered, fever and flue-like syndrome were common side effects. Grade I fever and flue-like syndrome 50~150 pg/m dose, and grade II fever flue- like syndrome were observed at the dose of grater than 250 u/m(2)/d dose. Even at the 700 ug/m(2)/ d dose, no greater than grade III toxicities were observed. Leucocytosis were dose dependent with 120-480% increment of baseline. Pharmacokinetic parameters are as follows; Cmax were dose dependent(0.42-11.7 ng/ml) with 2-4 hours of Tmax. AUC were also dose dependent(3.93~87.9ng.hr/ml) with sustained serum levels(0.2-2ng/ml) up to 12 hours after rh GM-CSF administration. Urinary excretion(0-24 hours) after GM-CSF was less than 1% of administered dose. Yeast-derived rh GM-CSF induces leucocytosis in the dose range of 150~500ug/m(2)/d with tolerable side effects. Subcutaneously administered rh GM-CSF has sustained serum levels up to 12 hours after administration. The doses of 150-500 ug/m/d would be appropriated for the further trials.