Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours.
Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m(-2) every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m(-2). With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m(-2) followed by losoxantrone 95 mg m(-2) with granulocyte colony-stimulating factor support.
Goh
B C
BC
Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, Illinois, IL 60637, USA.
Vokes
E E
EE
Joshi
A
A
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000880:Anthraquinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D009504:Neutrophils / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D047069:Pyrazolones
D000880:Anthraquinones; D011720:Pyrazoles; D047069:Pyrazolones; D016179:Granulocyte Colony-Stimulating Factor; C050637:losoxantrone; D003520:Cyclophosphamide