Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors
| Autor: | Nicholas J. Patronas, Timothy O'Toole, Peter C. Adamson, Mahendra C. Patel, Alberta A. Aikin, Katherine E. Warren, David Benziger, Madeleine Libucha, Brigitte C. Widemann, Rachel B. Neuwirth, Kathleen Ford, Roger J. Packer, Frank M. Balis |
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| Rok vydání: | 2001 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Neutropenia Adolescent medicine.medical_treatment Urology Renal function Toxicology Bradykinin Lobradimil Carboplatin chemistry.chemical_compound Refractory Pharmacokinetics Seizures medicine Flushing Humans Pharmacology (medical) Child Infusions Intravenous Pharmacology Chemotherapy Dose-Response Relationship Drug business.industry Brain Neoplasms Headache medicine.disease Thrombocytopenia Oncology chemistry Blood-Brain Barrier Anesthesia Area Under Curve Child Preschool Toxicity Drug Therapy Combination Female Hypotension business |
| Zdroj: | Cancer chemotherapy and pharmacology. 48(4) |
| ISSN: | 0344-5704 |
| Popis: | Purpose: 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. |
| Databáze: | OpenAIRE |
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