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


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.


CONCLUSIONS
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.
Savarese
D M
DM
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Denicoff
A M
AM
Berg
S L
SL
Hillig
M
M
Baker
S P
SP
O'Shaughnessy
J A
JA
Chow
C
C
Otterson
G A
GA
Balis
F M
FM
Poplack
D G
DG
D000328:Adult; D000368:Aged; D000880:Anthraquinones / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011720:Pyrazoles; D016179:Granulocyte Colony-Stimulating Factor; C046659:piroxantrone