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Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer


Basser, RL; Rasko, JEJ; Clarke, K; Cebon, J; Green, MD; Grigg, AP; Zalcberg, J; Cohen, B; OByrne, J; Menchaca, DM; Fox, RM; Begley, CG
1997-05-01
BLOOD
Journal Article
89
9
3118-3128
Thrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m(2) and cyclophosphamide 1,200 mg/m(2) were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 pg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days, All patients received concurrent filgrastim 5 mu g per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo, The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P=.002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 mu g/ kg versus 22 days for placebo, P=.014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 mu g/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation. (C) 1997 by The American Society of Hematology.
W B SAUNDERS CO
COLONY-STIMULATING FACTOR; BLOOD PROGENITOR CELLS; OVARIAN-CANCER; INDUCED THROMBOCYTOPENIA; PLATELET RECOVERY; CARBOPLATIN; CISPLATIN; THERAPY; MICE
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Creation Date 1997-05-01 12:00:00