Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme

Purpose: To determine the safety, pharmacokinetics, and pharmacodynamic eff ect of 2-[4-(3,5-dimethylanilino)carbonyl]methyl]phenoxyl-2-methylproprioni c acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma mul tiforme (GBM), RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby re ducing oxygen binding affinity and increasing tissue oxygen release to hypo xic tissues. Patients and Methods: In this multi-institutional, dose frequency-seeking t rial, 19 adult patients with newly diagnosed GEM received RSR 13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions), RSR13 was given over 1 hour by central venous access with 4 L/min of O-2 by nasal cannula, followed by RT within 30 minutes, pharmacokinetic (PK) and pharma codynamic (PD) determinations were performed, The PD end point was shift in P50, the oxygen half-saturation pressure of HgB, Results: Grade 3 dose-limiting toxicity occurred in none of the patients wi th every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10 , respectively, PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related ta RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 +/- 2.6 mmHg (a 34% increase from baseline) , which indicates a substantial increase in tendency toward oxygen unloadin g. Conclusion: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for new ly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to det ermine survival outcome. (C) 1999 by American Society of Clinical Oncology.