Targeted downregulation of TGF-beta2 as immunotherapy for high-grade glioma: A phase IIb study

Abstract

1537 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. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma GmbH Antisense Pharma GmbH Antisense Pharma, Antisense Pharma GmbH