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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
RL Basser, JE Rasko, K Clarke, J Cebon, MD Green, AP Grigg, J Zalcberg, B Cohen, J O'Byrne, DM Menchaca, RM Fox and CG Begley
Centre for Developmental Cancer Therapeutics, Parkville, Victoria,
Australia.
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.
Volume 89,
Issue 9,
pp. 3118-3128,
05/01/1997
Copyright © 1997 by The American Society of Hematology
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