title: 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.
abstract: 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/m2 and cyclophosphamide 1,200 mg/m2 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 microg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 microg 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 microg/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 microg/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.
authors.affiliation: Centre for Developmental Cancer Therapeutics, Parkville, Victoria, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Basser
authors.forename: J E
authors.initials: JE
authors.lastname: Rasko
authors.forename: K
authors.initials: K
authors.lastname: Clarke
authors.forename: J
authors.initials: J
authors.lastname: Cebon
authors.forename: M D
authors.initials: MD
authors.lastname: Green
authors.forename: A P
authors.initials: AP
authors.lastname: Grigg
authors.forename: J
authors.initials: J
authors.lastname: Zalcberg
authors.forename: B
authors.initials: B
authors.lastname: Cohen
authors.forename: J
authors.initials: J
authors.lastname: O'Byrne
authors.forename: D M
authors.initials: DM
authors.lastname: Menchaca
authors.forename: R M
authors.initials: RM
authors.lastname: Fox
authors.forename: C G
authors.initials: CG
authors.lastname: Begley
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D010919:Placebos; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013926:Thrombopoietin / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D010919:Placebos; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D003520:Cyclophosphamide; D013926:Thrombopoietin; D016190:Carboplatin; D000069585:Filgrastim