Evaluation of safety and tolerance of escalating doses of RSR13 administered with a fixed dose of BCNU every six weeks in patients with recurrent malignant glioma: Results of the phase I NABTT 9806 clinical trial

Abstract

1533 Background: RSR13 is an allosteric modifier of hemoglobin which has been shown to increase tumor oxygen delivery, with potential to improve cytotoxic therapy. Previous studies in glioblastoma have demonstrated that the agent is tolerable at 100 mg/kg when delivered daily prior to radiotherapy, and survival was reported in excess of one year. Preclinical studies have shown enhancement of the response to certain chemotherapeuticagents as well. This protocol is assessing the safety and tolerance of escalating doses of RSR13 when administered prior to BCNU in patients with recurrent high grade glioma, as well as maximum tolerated dose and pharmacokinetics of RSR13 when administered with BCNU. Methods: RSR13, in escalating doses of 25 mg/kg, to a maximum of 100 mg/ kg, in cohorts of six patients each, was administered over 30 minutes prior to infusion of BCNU 200 mg., every six weeks, for a maximum of six cycles. Only nonhematologic toxicities are assessed in determining the dose limiting toxicity (DLT) of the combination of agents. Results: A total of 33 patients have been accrued, 14 females, 19 males. Two grade 3/4 hematologic toxicities occurred in the first cohort of six patients at 25 mg/kg, therefore this cohort was expanded to 12. One non-hematologic DLT was observed in this cohort (generalized weakness) and in the 50 mg/kg cohort, a DLT of pulmonary edema was observed. There were no DLTs in the 75 mg/kg cohort. Symptomatic hypoxia was observed as a significant adverse event in two patients in the 100 mg/kg cohort which is still enrolling. Conclusions: Hematologic toxicity is manageable in this drug combination. The maximum tolerated dose of RSR13 with BCNU is projected to be 75 or 100 mg/kg. No significant financial relationships to disclose.