Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics 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 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). RESULTS: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the 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 patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. CONCLUSIONS: The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Comparison of one-, two-, and three-dimensional measurements of childhood brain tumors.

BACKGROUND: End points for assessing drug activity in brain tumors are determined by measuring the change in tumor size by magnetic resonance imaging (MRI) relative to a pretreatment or best-response scan. Traditionally, two-dimensional (2D) tumor measurements have been used, but one-dimensional (1D) measurements have recently been proposed as an alternative. Because software to estimate three-dimensional (3D) tumor volume from digitized MRI images is available, we compared all three methods of tumor measurement for childhood brain tumors and clinical outcome. METHODS: Tumor size from 130 MRI scans from 32 patients (32 baseline and 98 follow-up scans, for a total of 130 scans; median, three scans per patient; range, two to 18 scans) was measured by each method. Tumor-response category (partial response, minor response, stable disease, or progressive disease) was determined from the percentage change in tumor size between the baseline or best-response scan and follow-up scans. Time to clinical progression was independently determined by chart review. All statistical tests were two-sided. RESULTS: Concordances between 1D and 2D, 1D and 3D, and 2D and 3D were 83% (95% confidence interval [CI] = 67% to 99%), 61% (95% CI = 47% to 75%), and 66% (95% CI = 52% to 80%), respectively, on follow-up scans. Concordances for 1D and 3D and for 2D and 3D were statistically significantly lower than the concordance for 1D and 2D (P< .001 and P = .003, respectively). Concordance among 1D, 2D, and 3D methods in detecting partial response was high; there was less concordance in classifying tumors in the minor response and progressive-disease categories. Median times to progression measured by the 1D, 2D, and 3D methods were 154, 105, and 112 days, respectively, compared with 114 days based on neurologic symptoms and signs (P = .09 for overall comparison). CONCLUSIONS: Detection of partial responses was not influenced by the measurement method, but estimating time to disease progression may be method dependent for childhood brain tumors.

Proton magnetic resonance spectroscopic imaging in children with recurrent primary brain tumors.

PURPOSE: Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) is a noninvasive technique for spatial characterization of biochemical markers in tissues. We measured the relative tumor concentrations of these biochemical markers in children with recurrent brain tumors and evaluated their potential prognostic significance. PATIENTS AND METHODS: (1)H-MRSI was performed on 27 children with recurrent primary brain tumors referred to our institution for investigational drug trials. Diagnoses included high-grade glioma (n = 10), brainstem glioma (n = 7), medulloblastoma/peripheral neuroectodermal tumor (n = 6), ependymoma (n = 3), and pineal germinoma (n = 1). (1)H-MRSI was performed on 1. 5-T magnetic resonance imagers before treatment. The concentrations of choline (Cho) and N-acetyl-aspartate (NAA) in the tumor and normal brain were quantified using a multislice multivoxel method, and the maximum Cho:NAA ratio was determined for each patient's tumor. RESULTS: The maximum Cho:NAA ratio ranged from 1.1 to 13.2 (median, 4.5); the Cho:NAA ratio in areas of normal-appearing brain tissue was less than 1.0. The maximum Cho:NAA ratio for each histologic subtype varied considerably; approximately equal numbers of patients within each tumor type had maximum Cho:NAA ratios above and below the median. Patients with a maximum Cho:NAA ratio greater than 4.5 had a median survival of 22 weeks, and all 13 patients died by 63 weeks. Patients with a Cho:NAA ratio less than or equal to 4.5 had a projected survival of more than 50% at 63 weeks. The difference was statistically significant (P =.0067, log-rank test). CONCLUSION: The maximum tumor Cho:NAA ratio seems to be predictive of outcome in children with recurrent primary brain tumors and should be evaluated as a prognostic indicator in newly diagnosed childhood brain tumors.