title: Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases.
abstract: PURPOSE: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients. EXPERIMENTAL DESIGN: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m(2) temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m(2) temozolomide daily for 5 of every 28 days). Patients previously treated with temozolomide were enrolled on arm C: extended dosing of temozolomide. Patients with brain metastases and no prior temozolomide were assigned to arm D: standard dosing. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included response rate, toxicity rates, and the rates of BRAF or NRAS mutations. RESULTS: The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3 to 4 lymphopenia in arm A. CONCLUSION: Temozolomide plus sorafenib was well tolerated and showed activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. (Clin Cancer Res 2009;15(24):7711-8).
authors.affiliation: Authors' Affiliations: Abramson Cancer Center at the University of Pennsylvania and Department of Medicine, Division of Medical Genetics, University of Pennsylvania, Philadelphia, Pennsylvania; and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.forename: Amy
authors.initials: A
authors.lastname: Kramer
authors.forename: Lydia
authors.initials: L
authors.lastname: Giles
authors.forename: Kristi
authors.initials: K
authors.lastname: Gramlich
authors.forename: Mary
authors.initials: M
authors.lastname: Carberry
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Troxel
authors.forename: Richard
authors.initials: R
authors.lastname: Letrero
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty