Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.
BACKGROUND
[corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression.


METHODS
Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle.


RESULTS
Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma.


CONCLUSIONS
The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
Warren
K
K
National Cancer Institute/Neuro-Oncology Branch, Bethesda, MD 20892-8200, USA. warrenk@mail.nih.gov
Jakacki
R
R
Widemann
B
B
Aikin
A
A
Libucha
M
M
Packer
R
R
Vezina
G
G
Reaman
G
G
Shaw
D
D
Krailo
M
M
Osborne
C
C
Cehelsky
J
J
Caldwell
D
D
Stanwood
J
J
Steinberg
S M
SM
Balis
F M
FM
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001920:Bradykinin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004334:Drug Administration Schedule; D006801:Humans; D007262:Infusions, Intravenous; D016896:Treatment Outcome
C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin