A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies

Chow, Laura Q. M., Gustafson, Daniel L., O'Bryant, Cindy L., Gore, Lia, Basche, Michele, Holden, Scott N., Morrow, Mark C., Grolnic, Stacy, Creese, Brian R., Roberts, Kaye L., Davis, Kat, Addison, Russell and Eckhardt, S. Gail (2008) A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies. Cancer Chemotherapy and Pharmacology, 63 1: 65-74. doi:10.1007/s00280-008-0712-z

Author Chow, Laura Q. M.
Gustafson, Daniel L.
O'Bryant, Cindy L.
Gore, Lia
Basche, Michele
Holden, Scott N.
Morrow, Mark C.
Grolnic, Stacy
Creese, Brian R.
Roberts, Kaye L.
Davis, Kat
Addison, Russell
Eckhardt, S. Gail
Title A phase I pharmacological and biological study of PI-88 and docetaxel in patients with advanced malignancies
Journal name Cancer Chemotherapy and Pharmacology   Check publisher's open access policy
ISSN 0344-5704
Publication date 2008-12
Sub-type Article (original research)
DOI 10.1007/s00280-008-0712-z
Volume 63
Issue 1
Start page 65
End page 74
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
Purpose: This study evaluated the safety, toxicity, pharmacological properties and biological activity of PI-88, a heparanase endoglycosidase enzyme inhibitor, with fixed weekly docetaxel in patients with advanced solid malignancies.

Experimental design:
This was a phase I study to determine the maximal-tolerated dose of escalating doses of PI-88 administered subcutaneously for 4 days per week, along with docetaxel 30 mg/m2 given on days 1, 8, 15 of a 28-day schedule.

Results: Sixteen patients received a total of 42 courses of therapy. No dose-limiting toxicities were observed despite escalation to the highest planned dose level of PI-88 (250 mg/day). Frequent minor toxicities included fatigue (38%), dysgeusia (28.5%), thrombocytopenia (12%), diarrhea (14%), nausea (12%), and emesis (10%) in the 42 courses. No significant bleeding complications were observed. One patient developed a positive anti-heparin antibody test/serotonin releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae. PI-88 plasma concentrations (mirrored by APTT) and urinary elimination were linear and dose-proportional. Docetaxel did not alter the pharmacokinetic (PK) proWle of PI-88, nor did PI-88 affect  docetaxel PK. No significant relationship was determined between plasma or urine FGF-2, or plasma VEGF levels and PI-88 dose/response. Although no objective responses were observed; 9 of the 15 evaluable patients had stable disease for greater than two cycles of therapy.

Conclusion: PI-88 administered at 250 mg/day for 4 days each week for 3 weeks with docetaxel 30 mg/m2 on days 1, 8 and 15, every 28 days, was determined to be the recommended dose level for phase II evaluation. This combination was well tolerated without severe toxicities or PK interactions.
Keyword PI-88
Heparanase inhibitor
Clinical trial
Advanced malignancies
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 11 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 03 Sep 2009, 09:30:51 EST by Mr Andrew Martlew on behalf of School of Pharmacy