Alfred Wieder AG ( Seite 6)

Meeting: 2003 ASCO Annual Meeting
Category: Central Nervous System Tumors
SubCategory: CNS Tumors



A TGF-beta2 specific antisense oligonucleotide (AP12009) as continuous intratumoral treatment of recurrent high-grade glioma patients: A clinical phase I/II extension study
Abstract No: 436
Citation: Proc Am Soc Clin Oncol 22: page 109, 2003 (abstr 436)
Author(s): G. M. Stauder, P. Hau, U. Bogdahn, A. Steinbrecher, A. Brawanski, J. Schlaier, G. Wurm, J. Pichler, M. Kunst, K.-H. Schlingensiepen ; Antisense Pharma GmbH, Regensburg, Germany ; Dept. Neurology, University Regensburg, Regensburg, Germany; Dept. Neurosurgery, University Regensburg, Regensburg, Germany; Dept. Neurosurgery, Wagner-Jauregg, Linz, Austria
Abstract: In a previous phase I/II dose escalation study, patients with high-grade glioma had been treated intratumorally with a single course of TGF-beta2 antisense phosphorothioate oligonucleotide AP12009 and demonstrated an excellent safety and tolerability. In this study, a continuous infusion of up to ten courses of AP12009 - alternating with NaCl infusion during the intervals - was applied to 7 patients. AP12009 was developed to block the mRNA of transforming growth factor beta2 (TGF-beta2), which is known to correlate with bad prognosis in high-grade glioma. The inclusion criteria were identical to the preceding study: adult patients with recurrent high-grade glioma and evidence of tumor progression on MRI despite previous therapies. The highest dose in the first study was chosen for one cohort in this study; in the second cohort the duration of the active drug periods was prolonged, using the same daily dose, thus increasing the total dose per course once more. Both AP12009 and NaCl were applied by high-flow microperfusion, with the intratumoral implanted catheter connected with an indwelling tube and a subcutaneous port to an external pump, delivering the substances with a continuous flow. During intervals, NaCl was applied with a very low flow rate, to inhibit blocking of the intratumoral catheter tip. In the first already completed cohort, no drug related relevant side effects were documented in any patient, as evaluated by an independent data and safety monitoring board (DSMB). An update will be given on survival of the 18 patients treated with AP12009 in the first study: as per December 19th, 2002, the median overall survival of patients with anaplastic astrocytoma (AA) after recurrence is 77 weeks, and 47 weeks for glioblastoma (GBM) patients. The figures for the 13 patients having received temozolomide as chemotherapy before AP12009 are 112 weeks for AA, and 61 weeks for GBM, respectively. One patient having shown a nearly complete response is still alive 183 weeks after the recurrence following only one course of AP 12009 therapy (data will be updated at the congress).



Meeting: 2004 ASCO Annual Meeting
Category: Central Nervous System Tumors
SubCategory: CNS Tumors



Specific therapy for high-grade glioma by convection-enhanced delivery of the TGF-β2 specific antisense oligonucleotide AP 12009.
Abstract No: 1514
Citation: Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 1514
Author(s): 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
Abstract: 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.


Meeting: 2005 ASCO Annual Meeting
Category: Central Nervous System Tumors
SubCategory: CNS Tumors



Targeted downregulation of TGF-beta2 as immunotherapy for high-grade glioma: A phase IIb study
Abstract No: 1537
Author(s): P. Hau, M. Kunst, J. Pichler, V. Parfenov, K. Sastry, L. Spitznagel, M. Zaaroor, U. Bogdahn, K. Schlingensiepen , AP 12009 Glioma Study Group
Abstract: Background: High-grade (malignant) glioma are highly aggressive tumors showing marked overexpression of transforming growth factor-beta2 (TGF-beta2). TGF-beta plays a key role in malignant progression by inducing proliferation, invasion and metastasis, angiogenesis and immunosuppression and is responsible for the immunodeficient state of malignant glioma patients. AP 12009, a phosphorothioate antisense oligodeoxynucleotide specific for the human TGF-beta2 mRNA, has been developed as a targeted anti-tumor therapy. AP 12009 has already proven safety and shown anti-tumor activity in phase I/II clinical studies as therapy for recurrent high-grade glioma after intratumoral infusion. Methods: Based on the successful phase I/II studies with AP 12009 a phase IIb multinational study in adult patients with recurrent high-grade glioma, i.e. Anaplastic Astrocytoma (AA), WHO grade III, and Glioblastoma Multiforme (GBM), WHO grade IV, is currently ongoing. Patients are randomized into 3 treatment groups to receive either one of two doses of AP 12009 or standard chemotherapy, i.e. temozolomide, or the combination Procarbazine/CCNU/Vincristine (PCV). The primary objectives of this open label, phase IIb study are response rate (RR), progression free survival (PFS) and overall survival at different time points. AP 12009 is administered intratumorally as continuous high-flow microperfusion for 7 days every other week for up to 11 cycles. Both, efficacy and safety will be used as criteria for evaluation. Results and Conclusion: In the previous phase I/II studies the median overall survival time was longer than the one reported in the recent literature (Yung et al, 2000, Theodosopoulus et al, 2001, Chang et al, 2004) on standard chemotherapy. Data on anti-tumor activity in phase I/II studies with 24 patients included several patients with stabilizations and two patients with complete tumor remissions, both of them long-lasting without recurrence. In the current phase IIb study more than 120 patients have been enrolled. Based on the clinical data in malignant glioma and very encouraging preclinical results in pancreatic carcinoma AP 12009 is now in phase I/II studies in pancreatic carcinoma as its second tumor indication.[b/]

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Für alle leischaftlich Ahnungslosen Poster in diesem Thread:

Die Ergebnisse aus der Studie II b dürften im Februar/März 2006 veröffentlicht werden.

Vielleicht "krebst" ihr auch mal auf der Homepage der Anitsense Pharma (www.antisense-pharma.com) herum.

Man Leute, ein wenig ernsthafte Recherche und erst dann den Mund aufmachen!

Tackerin