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Specific therapy for high-grade
glioma by convection-enhanced delivery of the TGF-β2 specific antisense
oligonucleotide AP 12009
U. Bogdahn, P. Hau, A. Brawanski, J. Schlaier, M. Mehdorn, G. Wurm, J.
Pichler, M. Kunst, G. Stauder, K.-H. Schlingensiepen
Klinik und Poliklinik für Neurologie, Regensburg, Germany; Klinik und
Poliklinik für Neurochirurgie, Regensburg, Germany; Universitätsklinikum
Schleswig-Holstein, Kiel, Germany; Landesnervenklinik Wagner-Jauregg, Linz,
Austria; Antisense Pharma GmbH, Regensburg, Germany
Background.
High-grade gliomas are highly aggressive tumors showing marked transforming
growth-factor-beta2 (TGF-β2) overexpression inducing proliferation,
metastasis, angiogenesis and in particular immunosuppression.
Methods.
In 3 phase I/II dose escalation studies adult high-grade glioma patients (WHO
III/IV) with recurrent tumor and evidence of tumor progression on MRI were
treated with AP 12009, a TGF-β2 specific phosphorothioate antisense
oligonucleotide.
AP 12009 was administered intratumorally by convection enhanced delivery (CED)
in 3 studies in up to 12 cycles.
In the 3rd study, an indwelling pump system was used that allowed repeated
treatment cycles with a single catheter placement on an out-patient basis.
Safety and tolerability were primary endpoints.
Secondary endpoint was clinical efficacy.
Results.
In only 5 of the total 24 patients “possibly” related adverse events were
observed, mostly of grade 1 or 2, one was classified as serious.
There were no relevant changes in laboratory values, including hematology.
Application system and CED were tolerated without problems.
Efficacy evaluation resulted in a median overall survival time (mOS) of patients
with anaplastic astrocytoma (AA) from start of the first chemotherapy after
recurrence of 97.4 weeks, and 44.0 weeks for glioblastoma (GBM) patients as
compared to the published data for temozolomide therapy of 42 (AA) and 32 weeks
(GBM), respectively.
One AA patient had a complete response in all tumor sites after 1 cycle of AP
12009 experiencing an overall survival of 195 weeks after first
recurrence.
A similar tumor reduction of more than 80% with nearly identical time course was
documented for a second AA patient receiving 12 cycles of AP 12009.
Additionally, one GBM patient showed a strong reduction in tumor size.
Conclusions.
These results show AP 12009 mediated TGF-β2 suppression to be a highly
promising therapeutic approach for TGF-β overexpressing tumors such as
high-grade gliomas.
Thus, AP 12009 is now applied in an international phase II/III study in
comparison to standard chemotherapy.
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_19-001924,00.asp
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