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A TGF-beta2 specific antisense oligonucleotide (AP12009) as continuous intratumoral treatment of recurrent high-grade glioma patients: A clinical phase I/II extension study
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
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 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).
ASCO 2003 Abstract No: 436 Category: CNS Tumors