title: Phase I trial to determine the safety, pharmacodynamics, and pharmacokinetics of RSR13, a novel radioenhancer, in newly diagnosed glioblastoma multiforme.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  In this multi-institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 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 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 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD, USA. kleinla@jhmi.edu
authors.forename: L
authors.initials: L
authors.lastname: Kleinberg
authors.forename: S A
authors.initials: SA
authors.lastname: Grossman
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: J
authors.initials: J
authors.lastname: Pearlman
authors.forename: H
authors.initials: H
authors.lastname: Engelhard
authors.forename: G
authors.initials: G
authors.lastname: Lesser
authors.forename: J
authors.initials: J
authors.lastname: Ruffer
authors.forename: M
authors.initials: M
authors.lastname: Gerber
mesh_terms: D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000986:Antisickling Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000401:mortality / Q000532:radiotherapy*; D005909:Glioblastoma / Q000401:mortality / Q000532:radiotherapy*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D011422:Propionates / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011856:Radiographic Image Enhancement; D016019:Survival Analysis
chemical_list: D000814:Aniline Compounds; D000986:Antisickling Agents; D006454:Hemoglobins; D011422:Propionates; C067396:efaproxiral