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

Background: Tumor derived transforming growth factor beta (TGF-beta) is a pivotal factor for malignant progression by inducing metastasis, angiogenesis, tumor cell proliferation and immunosuppression. High-grade gliomas are highly aggressive tumors showing marked overexpression of the TGF-beta2 isoform which is correlated with advanced tumor stage.

Methods: In 3 phase I/II dose escalation studies adult high-grade glioma patients (WHO grades III/IV) with recurrent tumor and evidence of tumor progression on MRI were treated with AP 12009, a TGF-beta2 specific phosphorothioate antisense oligonucleotide. AP 12009 was administered intratumorally by convection enhanced delivery (CED) in up to 12 cycles. In the 3rd study, an indwelling pump system was used allowing 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. Alternatively, this event could also be related to rapid reduction of steroids performed in this patient prior to study entry. There were no relevant changes in laboratory values, including hematology. Application system and CED were well 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 132.6 weeks, and 46.1 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 one cycle of AP 12009 experiencing an overall survival of 195 weeks after first recurrence. A similar tumor remission of more than 90% with similar time course was documented for a second AA patient receiving 12 cycles of AP 12009, and the remaining enhancing lesion was considered to be most likely scar tissue by the responsible neuroradiologist. Additionally, one GBM patient showed a strong reduction in tumor size.

Conclusions: These results show AP 12009 mediated TGF-beta2 suppression to be a highly promising therapeutic approach for TGF-beta overexpressing tumors such as high-grade gliomas. Thus, AP 12009 is now applied in comparison to standard chemotherapy in an international phase II/III study with currently 29 study centers.