title: A phase I study of pegylated liposomal doxorubicin and temsirolimus in patients with refractory solid malignancies.
abstract: This study aimed to determine the maximum-tolerated dose and dose-limiting toxicities of pegylated liposomal doxorubicin (PLD) in combination with temsirolimus (T) in patients with refractory solid tumors. Using a standard "3+3" dose escalation design, 23 patients were enrolled in three dosing cohorts in this phase I study. The starting dose level was PLD at 30 mg/m(2) every 4 weeks and T at 20 mg weekly. Pharmacokinetics (PK) of doxorubicin were evaluated for patients in the expansion cohort. The most common treatment-related adverse events of all grades were mucositis/stomatitis (69.6%), anorexia (52.2%), thrombocytopenia (52.2%), and fatigue (47.8%). The recommended doses of this combination for phase II studies are 25 mg/m(2) PLD and 25 mg T. PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent, possibly due to PK drug interactions. Out of 18 patients evaluable for a treatment response, two had partial responses (PR) (breast cancer and hepatocellular carcinoma) and six had stable disease (SD). Two patients remained on treatment for more than 1 year. The combination of PLD and T is tolerable, and the treatment resulted in clinical benefit. The combination regimen should be further explored in appropriate tumor types.
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.forename: Nilay
authors.initials: N
authors.lastname: Thakkar
authors.forename: A Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Kerry
authors.initials: K
authors.lastname: Williams
authors.forename: Maria
authors.initials: M
authors.lastname: Baggstrom
authors.forename: Michael
authors.initials: M
authors.lastname: Naughton
authors.forename: Rama
authors.initials: R
authors.lastname: Suresh
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tan
authors.forename: Wooin
authors.initials: W
authors.lastname: Lee
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
authors.forename: Tibu
authors.initials: T
authors.lastname: Mwandoro
authors.forename: Lauren
authors.initials: L
authors.lastname: Trull
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belanger
authors.forename: Allison N
authors.initials: AN
authors.lastname: Creekmore
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011379:Prognosis; D012449:Safety; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D014018:Tissue Distribution
chemical_list: C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; C401859:temsirolimus; D004317:Doxorubicin; D020123:Sirolimus