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Phase
I trial of intrathecal Spartaject busulfan for patients with neoplastic
meningitis
Jennifer
A Quinn, Michael Glantz, William Petros, Jeremy Rich, Howard Sands, Sandra
Tourt-Uhlig, Amy Walker, David Reardon, Sridharan Gururangan, John Sampson,
Allan Friedman, O. M Colvin, Henry Friedman
Duke
University Medical Center, Durham, NC; Neurological Research Center Inc,
Bennington, VT; Supergen, San Ramon, CA.
Busulfan,
a dimethanesulfonyloxyalkane, exhibits anti-tumor activity in preclinical
evaluations against medulloblastoma, high-grade gliomas, ependymomas,
cyclophosphamide-resistant neoplasms, and a spectrum of non-CNS tumor
histologies.
However, the marked insolubility of busulfan in an aqueous solution precludes
regional use of this alkylator.
A microcrystalline preparation of busulfan, SpartajectTM Busulfan, is
now available, with enhanced solubility allowing regional therapy with this
agent.
We now report a phase I clinical trial of intrathecal SpartajectTM
Busulfan in patients with neoplastic meningitis.
The study was designed to determine the maximum tolerated dose of intrathecal
SpartajectTM Busulfan in a limited escalation dose schedule, and to
determine the cerebrospinal fluid (CSF) and serum pharmacokinetics of this agent
administered via intralumbar or intraventricular routes.
Twenty-five patients have been enrolled in the study to date with four patients
receiving 2.5 mg, three patients receiving 5 mg, three patients receiving 7.5
mg, three patients receiving 10 mg, four patients receiving 13 mg, three
patients receiving 17 mg, and six patients receiving 21.25 mg of SpartajectTM
Busulfan.
Toxicity has been limited to seizures in one patient with recent resection of an
intracerebral metastasis.
The maximum tolerated dose has yet to be identified.
Pharmacokinetics are in progress but spot CSF samples obtained thirty minutes
after a 7.5 mg intraventricular injection revealed ventricular and lumbar
concentrations of 345 and 12 uM respectively.
Although the measurement of anti-tumor activity is not the primary objective of
this clinical trial, there is evidence that SpartajectTM Busulfan is
active against neoplastic meningitis.
Two patients with primary breast cancer, one patient with primary lung cancer,
and one patient with glioblastoma multiforme experienced a partial response, and
five patients experienced stable disease (2 weeks to 4 months).
© Copyright 2002
American
Society of Clinical Oncology
Source:
http://www.asco.org/ac/1,1003,_12-002324-00_18-002002-00_19-00318-00_29-00A-00_42-00ONeill-00_43-00-00_44-00-00_45-00
Author-00_46-00Title-00_47-00Title-00_48-00and-00_49-00and,00.asp?cat=CNS+Tumors&parent=CENTRAL+NERVOUS+SYSTEM+TUMORS
&returnpid=2323
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