Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.
ABSTRACT [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.
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.
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.
The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
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ABSTRACT: Rats implanted with RG-2 gliomas were administered i.v. RMP-7 and [14C]carboplatin. Changes in the permeability of the blood-brain barrier to carboplatin were determined using quantitative autoradiography. i.v. infusions of RMP-7 induced an increase in the permeability of the vascular barrier within the tumor to carboplatin. Additionally, permeability of brain tissue proximal to, but clearly outside the tumor mass, was also increased. Progressively less uptake of [14C]carboplatin was observed as distance from the tumor border increased. The increases in permeability induced by RMP-7 occurred in a dose-related fashion. No increase in carboplatin level was observed in several nonbrain tissues, including sciatic nerve, retina, heart, lung, liver, kidney, and spleen. Finally, the permeabilizing effects of RMP-7 were shown to occur independent of histaminergic or hypotensive mechanisms. These data provide additional insight into the permeabilizing effects and mechanism of RMP-7 and offer additional support for the therapeutic utility of this novel compound as an adjunctive treatment for human gliomas.Cancer Research 10/1996; 56(17):3998-4005. · 8.65 Impact Factor
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ABSTRACT: The primary objective of a phase II clinical trial of a new drug or regimen is to determine whether it has sufficient biological activity against the disease under study to warrant more extensive development. Such trials are often conducted in a multi-institution setting where designs of more than two stages are difficult to manage. This paper presents two-stage designs that are optimal in the sense that the expected sample size is minimized if the regimen has low activity subject to constraints upon the size of the type 1 and type 2 errors. Two-stage designs which minimize the maximum sample size are also determined. Optimum and "minimax" designs for a range of design parameters are tabulated. These designs can also be used for pilot studies of new regimens where toxicity is the endpoint of interest.Controlled Clinical Trials 04/1989; 10(1):1-10.
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ABSTRACT: The selective bradykinin analogue, RMP-7, transiently increases the permeability of the blood brain barrier and the delivery of hydrophilic agents into brain tumours. In 87 recurrent glioma patients (WHO Grade III/IV, median age 46, Karnofsky 70%) clinical and Magnetic Resonance Imaging (MRI) responses to i.v. cycles (q 28 days) of RMP-7 (300 ng/kg given as a 10 min infusion) and carboplatin (AUC 4-9) were assessed. 45 of these patients were chemotherapy naive (CN-RMP) and 42 had received one prior course of chemotherapy (CP-RMP). Neurological impairment, performance status and steroid use were measured prior to dosing at each cycle and tumour volume by 3-D MRI at the end of cycles 2, 4, 6, 9 and 12. Clinical evaluation of response demonstrated that 61% of CN-RMP patients were either stable or improved whilst this was 39% for CP-RMP patients, of which 37% and 8% improved respectively. Radiological evaluation showed 79% of CN-RMP patients were either stable, partial or complete responses and 24% for CP-RMP patients, of which 32% and 5% were CR or PR respectively. The median duration of response was 30.3 weeks in CN-RMP patients and 19.6 weeks in the CP-RMP group. Lack of response was associated with substantial baseline tumour volume. Drug toxicity was as previously reported for carboplatin. 11 patients had treatment-associated transient focal seizures. These results indicate that RMP-7 and carboplatin have significant activity in recurrent malignant glioma following radiotherapy.Journal of Neuro-Oncology 10/1999; 44(2):137-45. · 3.12 Impact Factor