title: A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor.
abstract: The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Kaplan Cancer Center, NYU Cancer Institute, New York University Medical Center, 462 First Avenue, BCD Room 556, New York, NY 10016, USA. pavlia01@gcrc.med.nyu.edu
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Catherine
authors.initials: C
authors.lastname: Chodkiewicz
authors.forename: Leonard
authors.initials: L
authors.lastname: Liebes
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.forename: Carolyn
authors.initials: C
authors.lastname: Wasserheit
authors.forename: Howard
authors.initials: H
authors.lastname: Hochster
authors.forename: James
authors.initials: J
authors.lastname: Speyer
authors.forename: Zoë
authors.initials: Z
authors.lastname: Phillips
authors.forename: Andrea
authors.initials: A
authors.lastname: Downey
authors.forename: Joan
authors.initials: J
authors.lastname: Sorich
authors.forename: Franco
authors.initials: F
authors.lastname: Muggia
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D017321:Clinical Trials, Phase I as Topic; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D008081:Liposomes; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D004317:Doxorubicin