|
|
Tgf-beta2 suppression by the antisense oligonucleotide ap 12009
as therapy for high-grade glioma: Safety and efficacy results of phase i/ii
clinical studies
Ulrich Bogdahn, Peter Hau, Alexander Brawanski, Juergen
Schlaier, Maximilian Mehdorn, Arya Nabavi, Gabriele Wurm, Josef Pichler,
Mechthild Kunst, Michael Goldbrunner, Gerhard Stauder, Gerhard Stauder,
Karl-Hermann Schlingensiepen
Department of Neurology, University of
Regensburg, Regensburg, Germany, Department of Neurosurgery, University of
Regensburg, Regensburg, Germany, Department of Neurosurgery, University of Kiel,
Kiel, Germany, Department of Neurosurgery, University of Linz, Linz, Austria,
Antisense Pharma GmbH, Regensburg, Germany. E-mail:
ulrich.bogdahn@bkr-regensburg.de
High-grade gliomas are highly aggressive tumors showing marked transforming
growth-factor-beta2 (TGF-beta2) overexpression.
TGF-beta plays a key role in
malignant progression by inducing proliferation, metastasis, angiogenesis and
immunosuppression.
TGF-beta2 appears to be responsible for the immunodeficient
state of glioma patients especially in later stages (Jachimczak et al. 1996,
Kjellman et al. 2000).
The TGF-beta2 specific phosphorothioate antisense
oligonucleotide AP 12009 was developed for the treatment of malignant gliomas.
In three phase I/II dose escalation studies adult high-grade glioma patients
(WHO grade III and IV) with recurrent tumor and evidence of tumor progression on
MRI were treated intratumorally with a single cycle (1st study), a second cycle
(2nd study), or up to ten cycles (3rd study) of AP 12009.
The primary endpoints
of these studies were safety and tolerability. The secondary endpoint was to
determine clinical efficacy.
In total, the dose was escalated 113-fold.
The therapy was applied
intratumorally by convection enhanced delivery (CED).
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.
Excellent safety and tolerability results were obtained in the studies: in
only 4 of the total 24 patients "possibly" related adverse events were
observed, mostly of grade 1 or 2.
There were no changes in laboratory values,
including hematology.
Safety data were evaluated by an independent Data and
Safety Monitoring Board.
Application system and CED were tolerated without
problems and well accepted by both patients and physicians.
In addition, the three studies have been evaluated for efficacy: as per
October 31st, 2003, the median overall survival time (mOS) of patients with
anaplastic astrocytoma (AA) from start of the first chemotherapy after
recurrence is 90.0 weeks, and 44.0 weeks for glioblastoma (GBM) patients as
compared to 42 (AA) and 32 weeks (GBM), respectively, the latter being the
published data for temozolomide therapy.
The mOS for the patient subgroup (n =
16) that received temozolomide as chemotherapy before AP 12009 is 146.6 weeks
for AA, and 46.1 weeks for GBM, respectively.
One patient had a complete
response in all tumor sites after one cycle of AP 12009.
Until his death due to
a myocardial infarction the patient experienced an overall survival of 195 weeks
after first recurrence.
A similar tumor reduction of more than 80% at present
with nearly identical time course was documented for a second patient receiving
12 cycles of AP 12009.
This patient is still alive. These results implicate AP
12009 mediated TGF-beta2 suppression as a highly promising therapeutic approach
for high-grade gliomas and other TGF-beta overexpressing tumors.
A clinical
study with AP 12009 in pancreatic carcinoma is currently in preparation.
Copyright © 2004 American Association for Cancer Research. All rights
reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=3546
|
