Phase I/II study with trabedersen (AP 12009) monotherapy for the treatment of patients with advanced pancreatic cancer, malignant melanoma, and colorectal carcinoma.

2513 Background: TGF-β2 regulates key cancer mechanisms, particularly immunosuppression and metastasis. The antisense oligonucleotide trabedersen (AP 12009) specifically inhibits TGF-β2 expression. A randomized, active-controlled Phase IIb study in high-grade glioma patients showed a clear survival benefit for trabedersen over standard chemotherapy. This study evaluates the maximum tolerated dose (MTD), safety, pharmakokinetics, and efficacy of intravenous trabedersen treatment in patients with advanced solid tumors. Methods: This open label, multicenter, Phase I/II study enrolled 33 patients with advanced pancreatic carcinoma (PanCa, stage III/IV, N=23), malignant melanoma (stage III/IV, N=5), or colorectal carcinoma (stage III/IV, N=5) into the dose-escalation part of the study. Patients were treated in cohorts with i.v. trabedersen monotherapy as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. In the Phase II-part of the study further PanCa and melanoma patients were treated with the 4d on, 10d off schedule with a dose of 140 mg/m2/d. The median overall survival of PanCa patients treated 2nd-line with the 2nd schedule-140 mg/m2/d regimen (N=9) has not yet been reached (12.9 months as of Dec 2010). One PanCa patient had a complete response of liver metastases and is still alive after 61 months (status Oct 2010). Further promising efficacy data from the dose-escalation are: one patient with metastatic and DTIC-resistant melanoma who is still alive 19.7 months after start of treatment (status Dec 2010); 3 other patients with stage IV melanoma, treated 3rd or 4th-line with trabedersen, who survived for 11.4, 13.8, and 18.6 months. Conclusions: Trabedersen showed excellent safety and encouraging survival results. The evaluation of 14 melanoma patients treated with the 4d on, 10d off-140 mg/m2/d regimen is ongoing. A randomized, active-controlled study in PanCA patients is in preparation.