A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma

Abstract

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

Phase I/II trial of pyrazoloacridine and carboplatin in patients with recurrent glioma: A North Central Cancer Treatment Group trial

“…Nevertheless, the percentage of patients with stable disease in our phase II study (38%) was comparable to prior single agent carboplatin trials [10,20]. The same applies for the median time to progression of 1.9 months observed in our study [22].…”

Low dose of bradykinin selectively increases intracellular calcium in glioma cells

“…Our recent clinical research showed that bradykinin B 2 receptors expression in glioma patients is positively correlated with the pathological grade of the glioma, but in each specific case, the expression pattern of B 2 receptors varies greatly [12]. The dose-dependent response to BK treatment suggests that the effect of BK treatment is correlated with the B 2 receptor expression level of the target cells; therefore we should screen patients according to their B 2 receptor expression levels in clinical RMP-7 trial study [13].…”

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

“…Another Phase II trial was conducted to investigate the effect in childhood high grade glioma and brainstem glioma, but also without effective results [135]. The lack of effectiveness in clinical trials has been attributed in part to the dose-limiting side effect of hypotension and to the differences between existing animal models and human patients [136]. The main drawback for the bradykinin analogs is that the effect of the receptors is exceedingly transient [127].…”

“…The main drawback for the bradykinin analogs is that the effect of the receptors is exceedingly transient [127]. Additionally, the non-uniform distribution of their receptors in the brain ultimately resulted in insufficient intracranial and intratumoral distribution of the anti-tumor compounds [136].…”