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

Thrombocytopenia caused by chemotherapy is an important cause of morbi dity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a p otent stimulator of megakaryocytopoiesis and prevents chemotherapy-ind uced thrombocytopenia in preclinical studies. We administered PEG-rHuM GDF with filgrastim after dose-intensive chemotherapy to 41 patients w ith advanced cancers to determine its safety and effects on hematologi c recovery. Carboplatin 600 mg/m(2) and cyclophosphamide 1,200 mg/m(2) were administered to patients with advanced cancer. Patients were ran domly assigned to receive blinded study drug, either PEG-rHuMGDF or pl acebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMG DF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 pg per kilo gram 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 re ceived PEG-rHuMGDF alone in a previous phase I study. platelet functio n and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuM GDF enhanced platelet recovery in a dose-related manner when compared with placebo, The platelet nadir occurred earlier in patients given PE G-rHuMGDF (P=.002) but there was no difference in the depth of the nad ir. Recovery to baseline platelet count was achieved significantly ear lier following PEG-rHuMGDF administration compared with placebo (media n, 17 days for PEG-rHuMGDF 0.3 to 5.0 mu g/ kg versus 22 days for plac ebo, P=.014). In addition, platelet recovery was faster in patients wh o had previously received PEG-rHuMGDF, suggesting that pretreatment mi ght be beneficial. Platelet function did not change during or after ad ministration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemothera py 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 pl atelet recovery after moderately dose-intensive carboplatin and cyclop hosphamide, and is likely to be clinically useful in treatment of chem otherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient colle ction of stem cells for autologous or allogeneic transplantation. (C) 1997 by The American Society of Hematology.