Phase 1 study of concurrent RMP-7 and carboplatin with radiotherapy for children with newly diagnosed brainstem gliomas.
BACKGROUND
Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to potentially improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing. However, delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The goal of the current Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy.


METHODS
RMP-7 was given before the end of carboplatin infusion. Local radiotherapy (5940 centigrays) was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion, in cohorts of 3, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, whose median age was 7 years (range, 3-14 yrs).


RESULTS
One child died early in treatment of progressive disease and was not assessable for toxicity. Treatment for 3, 4, or 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. Of 3 children treated at the full duration of therapy (33 doses over 7 wks), 1 developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival period was 328 days, and 1 patient remained disease progression free > 400 days from initiation of treatment.


CONCLUSIONS
The results of the current study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy.
Packer
Roger J
RJ
Division of Neurology, Children's National Medical Center, Washington, DC 20010, USA. rpacker@cnmc.org
Krailo
Mark
M
Mehta
Minesh
M
Warren
Katherine
K
Allen
Jeffrey
J
Jakacki
Regina
R
Villablanca
Judith G
JG
Chiba
Akiko
A
Reaman
Gregory
G
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001920:Bradykinin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D020295:Brain Stem Neoplasms / Q000401:mortality / Q000628:therapy*; D016190:Carboplatin / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005910:Glioma / Q000401:mortality / Q000628:therapy*; D006801:Humans
C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin