Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 1, pp 65–74 | Cite as

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

  • Laura Q. M. Chow
  • Daniel L. Gustafson
  • Cindy L. O’Bryant
  • Lia Gore
  • Michele Basche
  • Scott N. Holden
  • Mark C. Morrow
  • Stacy Grolnic
  • Brian R. Creese
  • Kaye L. Roberts
  • Kat Davis
  • Russell Addison
  • S. Gail Eckhardt
Original Article

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releasing assay with positive anti-platelet factor 4/PI-88 antibodies and grade 1 thrombocytopenia in cycle 5, and was withdrawn from the study without any sequelae.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) profile 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.

Keywords

PI-88 Docetaxel Heparanase inhibitor Angiogenesis Clinical trial Advanced malignancies 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Laura Q. M. Chow
    • 1
    • 4
  • Daniel L. Gustafson
    • 1
  • Cindy L. O’Bryant
    • 1
  • Lia Gore
    • 1
  • Michele Basche
    • 1
  • Scott N. Holden
    • 1
  • Mark C. Morrow
    • 1
  • Stacy Grolnic
    • 1
  • Brian R. Creese
    • 2
  • Kaye L. Roberts
    • 2
  • Kat Davis
    • 2
  • Russell Addison
    • 3
  • S. Gail Eckhardt
    • 1
  1. 1.University of Colorado Heath Sciences CenterAuroraUSA
  2. 2.Progen Pharmaceuticals LtdToowongAustralia
  3. 3.Tetra Q Integrated Preclinical Drug DevelopmentUniversity of QueenslandBrisbaneAustralia
  4. 4.The Ottawa Hospital Cancer CenterOttawaCanada

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