A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors.
OBJECTIVE
PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study.


METHODS
This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2).


RESULTS
Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months.


CONCLUSIONS
The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.
Basche
Michele
M
University of Colorado Cancer Center, Aurora, Colorado 80010, USA.
Gustafson
Daniel L
DL
Holden
Scott N
SN
O'Bryant
Cindy L
CL
Gore
Lia
L
Witta
Samir
S
Schultz
Mary Kay
MK
Morrow
Mark
M
Levin
Adrah
A
Creese
Brian R
BR
Kangas
Michael
M
Roberts
Kaye
K
Nguyen
Thu
T
Davis
Kat
K
Addison
Russell S
RS
Moore
Jane C
JC
Eckhardt
S Gail
SG
D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002276:Carcinoid Tumor / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006801:Humans; D007890:Leiomyosarcoma / Q000188:drug therapy; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009844:Oligosaccharides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D010314:Partial Thromboplastin Time; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000099175:Heparanase
D000970:Antineoplastic Agents; D005346:Fibroblast Growth Factors; D005966:Glucuronidase; D009844:Oligosaccharides; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C467484:VEGFA protein, human; C120158:phosphomannopentaose sulfate