TY - JOUR
T1 - Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme
AU - Kleinberg, Lawrence
AU - Grossman, S. A.
AU - Piantadosi, S.
AU - Pearlman, J.
AU - Engelhard, H.
AU - Lesser, G.
AU - Ruffer, J.
AU - Gerber, M.
PY - 1999/8
Y1 - 1999/8
N2 - Purpose: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4,(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2- methylproprionic acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. Patients and Methods: In this multi- institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR 13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over I hour by Central venous access with 4 L/rain of O2 by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (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 with even-other-day closing 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 to 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 unloading. 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 newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.
AB - Purpose: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4,(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2- methylproprionic acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. Patients and Methods: In this multi- institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR 13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over I hour by Central venous access with 4 L/rain of O2 by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (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 with even-other-day closing 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 to 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 unloading. 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 newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.
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U2 - 10.1200/jco.1999.17.8.2593
DO - 10.1200/jco.1999.17.8.2593
M3 - Article
C2 - 10561327
AN - SCOPUS:0032796232
SN - 0732-183X
VL - 17
SP - 2593
EP - 2603
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -