Specific
therapy for high-grade glioma by convection-enhanced delivery of the TGF-beta2
specific antisense oligonucleotide AP 12009
1Schlingensiepen, K.-H., 2Hau, P., 3Brawanski,
A., 3Schlaier, J., 4Mehdorn, M., 5Wurm, G.,
5Pichler, J., 1Jachimczak, P., 1Kunst, M.,
1Schlingensiepen, R., 1Stauder, G., and 2Bogdahn, U.
1 Antisense Pharma GmbH, Josef-Engert-Str.
9, 93053 Regensburg, Germany,
2 Klinik und Poliklinik für Neurologie der Universität
Regensburg im Bezirksklinikum, Universitätsstr. 84,
93053 Regensburg, Germany, 3 Klinik und Poliklinik für Neurochirurgie,
Universitätsklinik Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg,
Germany, 4 Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein,
Weimarer Str. 8, 24106 Kiel, Germany, 5 Landesnervenklinik Wagner-Jauregg,
Abteilung für Neurochirurgie, Wagner-Jauregg-Weg 15, 4020 Linz, Austria
e-mail: info@antisense-pharma.com
High-grade
gliomas are highly aggressive tumors showing marked transforming growth-factor-beta2
(TGF-b2) overexpression inducing proliferation, metastasis, angiogenesis and
in particular immunosuppression. 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-b2 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.
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. These results show
AP 12009 mediated TGF-b2 suppression to be a highly promising therapeutic
approach for TGF-b 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.