Phase I study of high-dose piroxantrone with granulocyte colony-stimulating factor

Diane M. F. Savarese, University of Massachusetts Medical School
Andrea M. Denicoff
Stacey L. Berg
Marianne Hillig
Stephen P. Baker, University of Massachusetts Medical School
Joyce A. O'Shaughnessy
Catherine Chow
Gregory A. Otterson
Frank M. Balis
David G. Poplack
Kenneth H. Cowan

Abstract

PURPOSE: We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone.

PATIENTS AND METHODS: Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2.

RESULTS: Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild.

CONCLUSION: The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines.