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KMID : 0360319940260030495
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Journal of Korean Cancer Research Association
1994 Volume.26 No. 3 p.495 ~ p.509
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Phase Ib Clinical Trial and Pharmacokinetic Evaluation of Recombinant Human Granulocyte-Macrophage Colony Stimulating Factor(rh GM-CSF, LBD-005) in Advanced Cancer Patinets with Chemotherapy Induced Myelosuppression
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노재경
최진혁/노형근/라선영/이경희/이혜란/김범수/한지숙/김병수
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Abstract
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To define the clinical safeties and hematologic effects of subcutaneously administered yeast-derived recombinant human granulocyte-macrophage colony stimulating factor(rh GM-CSF, LBD-005), 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, 700μg/㎡/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 500μg/㎡/d dose. At all the doses administered, fever and flue-like syndrome were common side effects. Grade I fever and
flue-like syndrome 50~150μg/㎡ dose, and grade Ⅱfever flue-like syndrome were observed at the dose of grater than 250μ/㎡/d dose. Even at the 700μg/㎡/d dose, no greater than gradeⅢtoxicities were observed. Leucocytosis were dose dependent
with
120~480% increment of baseline.
@ES Pharmacokinetic parameters are as follows;
@EN Cmax were dose dependent(0.42~11.7ng/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 150~500μg/㎡/d with tolerable side effects. Subcutaneously administered rh GM-CSF has sustained serum levels up to 12 hours after administration. The doses of 150~500μg/㎡/d
would
be
appropriated for the further trials.
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KEYWORD
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