Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.
OBJECTIVE
To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors.


METHODS
The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin.


RESULTS
There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies.


CONCLUSIONS
rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
Eder
Joseph P
JP
Division of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. jelder@partners.org
Supko
Jeffrey G
JG
Clark
Jeffrey W
JW
Puchalski
Thomas A
TA
Garcia-Carbonero
Rocio
R
Ryan
David P
DP
Shulman
Lawrence N
LN
Proper
Joann
J
Kirvan
Moira
M
Rattner
Barbara
B
Connors
Susan
S
Keogan
Mary T
MT
Janicek
Milos J
MJ
Fogler
William E
WE
Schnipper
Lowell
L
Kinchla
Nancy
N
Sidor
Carolyn
C
Phillips
Eric
E
Folkman
Judah
J
Kufe
Donald W
DW
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003094:Collagen / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003404:Creatinine / Q000378:metabolism; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000652:urine; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D008222:Lymphokines / Q000652:urine; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D003404:Creatinine