title: Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors.
  
  
  METHODS
  A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy).
  
  
  RESULTS
  Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability.
  
  
  CONCLUSIONS
  The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1928, USA. warrenk@exchange.nih.gov
authors.forename: K E
authors.initials: KE
authors.lastname: Warren
authors.forename: M C
authors.initials: MC
authors.lastname: Patel
authors.forename: A A
authors.initials: AA
authors.lastname: Aikin
authors.forename: B
authors.initials: B
authors.lastname: Widemann
authors.forename: M
authors.initials: M
authors.lastname: Libucha
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: R
authors.initials: R
authors.lastname: Neuwirth
authors.forename: D
authors.initials: D
authors.lastname: Benziger
authors.forename: T
authors.initials: T
authors.lastname: O'Toole
authors.forename: K
authors.initials: K
authors.lastname: Ford
authors.forename: N
authors.initials: N
authors.lastname: Patronas
authors.forename: R J
authors.initials: RJ
authors.lastname: Packer
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D001920:Bradykinin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D016190:Carboplatin / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005483:Flushing / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D012640:Seizures / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin