Preliminary results of a phase I/II study in pancreatic carcinoma, malignant melanoma, and colorectal carcinoma with the TGF- β2 inhibitor AP 12009

Abstract

4607 Background: TGF-β2 plays a pivotal role in tumor progression as it regulates key mechanisms, namely immunosuppression, metastasis, angiogenesis, and proliferation. The TGF-β2 inhibitor AP 12009 has shown clinical efficacy including complete and long-lasting remissions in patients with high-grade glioma. Methods: The currently ongoing clinical phase I/II study AP 12009-P001 is an open-label, multicenter, dose-escalation study. AP 12009 is being administered intravenously in adult patients with pancreatic carcinoma (PC, stage IVA/IVB), metastatic melanoma (MM, stage III/IV), or advanced colorectal carcinoma (CRC, stage III/IV). Primary endpoint is determination of the maximum tolerated dose (MTD). 3 to 6 patients per cohort (dose group) were enrolled into this dose escalation study. Results: So far, 17 patients have been treated in four dose groups, 11 patients with PC, 2 with MM, and 4 with CRC. Per cycle, AP 12009 was applied as a continuous i.v. infusion at weekly intervals in an out-patient setting. The 17 patients received one to ten cycles of AP 12009 (mean: 2.8). At the current stage, no (possibly) drug related serious adverse event (SAE), and only 17 (possibly) drug related adverse events (AEs) in eight patients have been observed. The 17 patients received one to ten cycles of AP 12009. Three dose-limiting toxicities (DLTs) occurred in the 4th dose group (exanthema grade 3 in one patient, thrombocytopenia grade 3 in two patients) and consequently, the MTD was determined as being 160 mg/m2/day with the current administration schedule. One patient suffering from MM stage IV is still alive 64 weeks after start of treatment. Moreover, one PC patient (stage IV) from the 2nd cohort is still after 72 weeks, having experienced a complete response. Further dose escalation studies in PC, MM, and CRC patients using a modified schedule are currently in preparation. Conclusions: In conclusion, encouraging case reports from the phase I/II study along with a good safety profile form a rational basis for the use of the TGF-β2 inhibitor AP 12009 as targeted therapy for advanced solid tumors such as PC, MM and CRC. No significant financial relationships to disclose.