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 et al., 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, Blood, 89(9), 1997, pp. 3118-3128
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.