title: Phase I trial of hepatic arterial infusion of nanoparticle albumin-bound paclitaxel: toxicity, pharmacokinetics, and activity.
abstract: Because liver involvement in patients with metastatic cancer has limited options and poor outcomes, we conducted a phase I study to determine the safety, activity, and pharmacokinetic characteristics of hepatic arterial infusion of nanoparticle albumin-bound paclitaxel (HAI nab-paclitaxel). Cohorts of three patients having predominant hepatic metastases received HAI nab-paclitaxel at three dose levels (180, 220, and 260 mg/m(2), respectively) infused for more than 1 hour every 3 weeks (3 + 3 design). Some patients participated in comparative pharmacokinetic studies (i.v. vs. HAI), receiving their first course i.v., to determine peak concentrations and effect of first-pass hepatic extraction compared with subsequent courses administered by HAI. The highest dose level was expanded to determine the safety and activity of HAI nab-paclitaxel. Thirty-eight patients were treated. There were no dose-limiting toxicities at doses up to 260 mg/m(2). Common adverse events included alopecia, fatigue, myelosuppresion, nausea, and vomiting. Three patients had stable disease for 4 or more months and 2 patients (1 of 12 with breast cancer and 1 of 1 with cervical cancer) achieved a partial response lasting for 5 and 15 months, respectively. Peak concentrations were lower (∼50%) with greater hepatic extraction of drug (∼42%) following HAI than i.v. infusion based on area under the curve comparison of drug exposure. HAI nab-paclitaxel showed partial hepatic extraction. At doses 260 mg/m(2) or less given for 1 hour every 3 weeks, the treatment was well-tolerated and showed activity in advanced cancer patients with predominant liver metastases.
authors.affiliation: Department of Investigational Cancer Therapeutics, Unit 0455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. siqingfu@mdanderson.org
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Kirk S
authors.initials: KS
authors.lastname: Culotta
authors.forename: David C
authors.initials: DC
authors.lastname: Madoff
authors.forename: Chaan S
authors.initials: CS
authors.lastname: Ng
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Madden
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000418:Albumins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D011859:Radiography; D016896:Treatment Outcome
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D017239:Paclitaxel