Interim results of the phase I/II study of trabedersen (AP 12009) in patients with pancreatic carcinoma, malignant melanoma, or colorectal carcinoma

4619 Background: TGF-beta 2 is one of the most potent immunosuppressors and mediates escape from immunosurveillance. It also plays a crucial role in tumor progression by regulating metastasis, angiogenesis, and proliferation. Trabedersen, a TGF-beta 2-specific inhibitor has already shown a clear survival benefit in a randomized active-controlled phase II study in high-grade glioma patients, compared to standard chemotherapy. Methods: 33 patients with advanced pancreatic carcinoma (stage IVA/IVB) (N=23), malignant melanoma (stage III/IV) (N=5) or colorectal carcinoma (stage III/IV) (N=5) were treated with trabedersen as 2nd-4th-line treatment. Two treatment schedules (1st schedule:7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles) were evaluated in a cohort dose-escalation design. Primary study objective: maximum tolerated dose (MTD); secondary objectives: safety and tolerability, pharmacokinetics and antitumor activity. Results: Patient recruitment for both schedules is completed. Very good safety and tolerability of trabedersen was observed, with moderate thrombocytopenia as main adverse event. Max. grade 3 dose-limiting toxicities (2 thrombocytopenias, 1 exanthema) occurring with 240 mg/m2/d in the 1st schedule established the MTD at 160 mg/m2/d. MTD has not been reached in the 2nd schedule. Of the 5 melanoma patients one from the 1st schedule showed stable disease and lived for 13.8 months; 3 patients from the 2nd schedule are still alive. Median overall survival (mOS) for pancreatic carcinoma patients in the 1st schedule was 6.8 months. One pancreatic carcinoma patient showed a complete response and is alive 38 months after trabedersen therapy. Current mOS for pancreatic carcinoma patients in cohort 1 (N=5) of the 2nd schedule is 13.2 months; 2 of these patients are alive, one with stable disease 14.8 months after begin of trabedersen treatment. Conclusions: Trabedersen has a very good safety and tolerability profile. The survival data are very encouraging. The study will continue with one dose in at least 12 patients. A randomized, active-controlled phase II study compared to standard therapy in patients with pancreatic carcinoma is in preparation; another one in malignant melanoma is being planned. [Table: see text]