Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies.

Autor: Reed DR; Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Adolescent and Young Adult Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; All Children's Hospital, Johns Hopkins Medicine, St. Petersburg, Florida., Mascarenhas L; Division of Hematology, Oncology, Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital of Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California., Manning K; Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Hale GA; All Children's Hospital, Johns Hopkins Medicine, St. Petersburg, Florida., Goldberg J; University of Miami, Miami, Florida., Gill J; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York., Sandler E; Nemours Children's Cancer Center, Jacksonville, Florida., Isakoff MS; Connecticut Children's Medical Center, Hartford, Connecticut., Smith T; Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Caracciolo J; Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Lush RM; Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Juan TH; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Lee JK; Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Neuger AM; Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida., Sullivan DM; Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.; Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Jazyk: angličtina
Zdroj: Cancer medicine [Cancer Med] 2016 Feb; Vol. 5 (2), pp. 294-303. Date of Electronic Publication: 2015 Dec 29.
DOI: 10.1002/cam4.598
Abstrakt: Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1-5 and 8-12 of each 28-day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m(2) and topotecan 1 mg/m(2) ; (2) sorafenib 150 mg/m(2) and topotecan 1.4 mg/m(2) ; and (3) sorafenib 200 mg/m(2) and topotecan 1.4 mg/m(2) . Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration-time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m(2) twice daily orally on days 1-28 combined with topotecan 1.4 mg/m(2) once daily on days 1-5 and 8-12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.
(© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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