Phase I trial of lobradimil (RMP-7) and carboplatin in children with braintumors

Citation
Ke. Warren et al., Phase I trial of lobradimil (RMP-7) and carboplatin in children with braintumors, CANC CHEMOT, 48(4), 2001, pp. 275-282
Citations number
16
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
4
Year of publication
2001
Pages
275 - 282
Database
ISI
SICI code
0344-5704(200110)48:4<275:PITOL(>2.0.ZU;2-H
Abstract
Purpose: To determine the maximum tolerated dose (MTD), the incidence and s everity of toxicities, and the pharmacokineties 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 2 8 days. The 10-min lobradimil infusion began 5 min before the end of the ca rboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/k g ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carb oplatin was adaptively dosed based on the glomerular filtration rate to ach ieve a target plasma area under the concentration-time curve (AUC) of 7.0 m g(.)min/ml per course (5.0 mg(.)min/ml for patients who had previously rece ived craniospinal radiation or myeloablative chemotherapy). Results: Lobrad imil toxicity was immediate, tolerable and rapidly reversible. The most fre quent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during th e 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 patien ts had stable disease. Myelosuppression (thrombocytopenia more prominent th an neutropenia) was the primary toxicity attributed to carboplatin. Lobradi mil pharmacokine tics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. Conclusions: The com bination of carboplatin and lobradimil is safe and tolerable. An MTD for lo bradimil was not defined because toxicity was not dose-related. The recomme nded pediatric phase II dose of lobradimil is 600 ng/kg IBW.