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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
P. Z. New, S. Grossman, T. Mikkelsen, T. Batchelor, S. Phuphanich, K. Carson,
J. Fisher, M. Craig, P. Cagnoni
Baylor College of Medicine, Houston, TX; Johns Hopkins Cancer
Center, Baltimore, MA; Henry Ford Hospital, Detroit, MI; Massachusetts General
Hospital, Boston, MA; Emory University, Atlanta, GA; Johns Hopkins Oncology
Center, Baltimore, MD; Johns Hopkins Cancer Center, Baltimore, MD; Allos
Therapeutics, Inc., Westminster, CO
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
chemotherapeutic agents 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.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-004367,00.asp
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