title: Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies.
abstract: 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.
authors.affiliation: 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.
authors.forename: Damon R
authors.identifier: http://orcid.org/0000-0002-8238-2465
authors.initials: DR
authors.lastname: Reed
authors.affiliation: 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.
authors.forename: Leo
authors.initials: L
authors.lastname: Mascarenhas
authors.affiliation: Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Manning
authors.affiliation: All Children's Hospital, Johns Hopkins Medicine, St. Petersburg, Florida.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hale
authors.affiliation: University of Miami, Miami, Florida.
authors.forename: John
authors.initials: J
authors.lastname: Goldberg
authors.affiliation: Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gill
authors.affiliation: Nemours Children's Cancer Center, Jacksonville, Florida.
authors.forename: Eric
authors.initials: E
authors.lastname: Sandler
authors.affiliation: Connecticut Children's Medical Center, Hartford, Connecticut.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Isakoff
authors.affiliation: Sarcoma Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Smith
authors.affiliation: Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Jamie
authors.initials: J
authors.lastname: Caracciolo
authors.affiliation: Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Lush
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Juan
authors.affiliation: 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.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Translational Research Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Neuger
authors.affiliation: 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.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib
keywords: Combination; pediatric cancer; phase I; sarcoma; sorafenib; topotecan