Phase I study of recombinant human endostatin in patients with advanced solid tumors.
OBJECTIVE
Endostatin, a 20-kd fragment of collagen XVIII, is a potent inhibitor of angiogenesis. We evaluated recombinant human endostatin (rh-Endo) in a phase I trial designed to assess safety, pharmacokinetics, and serum markers of angiogenesis in patients with solid tumors.


METHODS
Twenty-six patients were enrolled onto a dose-finding trial of rh-Endo administered as an intravenous bolus over a 20-minute period once daily. Three patients each were treated at dose levels of 15, 30, 60, 120, 180, and 600 mg/m(2)/d, and seven patients were treated at 300 mg/m(2)/d. Treatment consisted of a minimum of two 28-day cycles. Evaluations included noninvasive imaging, pharmacokinetics, and serum biomarkers.


RESULTS
Twenty-five patients were treated with rh-Endo. Treatment was well tolerated; there were no dose-limiting toxic effects. Bacteremia from frequent central line access was the most common problem. The pharmacokinetic disposition of rh-Endo was linear and best described using a two-compartmental open model. The overall mean half-life was 10.7 +/- 4.1 hours. A dose of 300 mg/m(2) achieved an area under the concentration-time curve associated with activity in preclinical models. In two patients, there was evidence of antitumor activity, but no responses were seen. Serum markers of angiogenic activity did not provide insight into rh-Endo's activity. Serum antibodies were observed against both rh-Endo and the Pichia pastoris vector, but no allergic reactions were observed.


CONCLUSIONS
rh-Endo was safe and well tolerated. rh-Endo pharmacokinetic profiles achieved area under the concentration-time curves associated with activity in preclinical models. Evidence of minor antitumor activity was observed and further studies are indicated.
Herbst
Roy S
RS
Department of Thoracic and Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Hess
Kenneth R
KR
Tran
Hai T
HT
Tseng
Jennifer E
JE
Mullani
Nizar A
NA
Charnsangavej
Chusilp
C
Madden
Timothy
T
Davis
Darren W
DW
McConkey
David J
DJ
O'Reilly
Michael S
MS
Ellis
Lee M
LM
Pluda
James
J
Hong
Waun K
WK
Abbruzzese
James L
JL
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003094:Collagen / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043170:Collagen Type XVIII; D019040:E-Selectin / Q000097:blood; D043169:Endostatins; D016228:Endothelial Growth Factors / Q000097:blood; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007262:Infusions, Intravenous; D008222:Lymphokines / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology; D010446:Peptide Fragments / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D014018:Tissue Distribution; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D019040:E-Selectin; D043169:Endostatins; D016228:Endothelial Growth Factors; D007136:Immunoglobulins; D008222:Lymphokines; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003094:Collagen