A Phase I study of concurrent RMP‐7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

Abstract

Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its 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 objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3-12 yrs). One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors.