Abstract 5506: Trabedersen (AP 12009) for the treatment of patients with advanced tumors: A phase I/II study

Abstract

Abstract Background: Transforming growth factor-beta 2 (TGF-β2) regulates key mechanisms of carcinogenesis, in particular immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized and active-controlled phase IIb study in high-grade glioma patients showed a clear survival benefit for intratumoral treatment with trabedersen over standard chemotherapy. In this study we evaluate the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors. Methods: In the open label, multicenter, Phase I/II study, 33 patients with advanced pancreatic carcinoma (PancCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) were enrolled in cohorts for dose-escalation. Patients were treated intravenously with trabedersen as 2nd to 4th-line therapy as monotherapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). After completion of dose-escalation, further patients were enrolled for the treatment with one defined dose in the Phase II part of the study. Results: Trabedersen showed excellent safety and tolerability. The only expected adverse reaction identified is non-serious, transient and moderate thrombocytopenia. Within the 1st schedule, MTD was established at a dose of 160 mg/m2/d. In the 2nd schedule (4d on, 10d off) a well tolerated dose (140 mg/m2/d) was identified and subsequently further 14 PancCa patients were treated with this regimen. The median overall survival of PancCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached and currently is 9.2 months (status Oct 2010). Further promising efficacy data include: one PancCa patient had a complete, sustained response of liver metastases and is alive 61 months after monotherapy with trabedersen; another patient is alive 31 months after treatment start (status Oct 2010). Promising efficacy was also observed in malignant melanoma patients with a current median overall survival of 13.8 months. Conclusions: Currently the study continues with the treatment of 12 patients with malignant melanoma with the 2nd schedule-140 mg/m2/d regimen. A randomized, active-controlled study in PancCA patients is in preparation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5506. doi:10.1158/1538-7445.AM2011-5506