Abstract 1293: A phase I dose-escalation study with pharmacokinetics (PK) of TriN 2755 in patients with advanced solid tumors: A study in cooperation with the Central European Society for Anticancer Drug Research (CESAR-EWIV)
Authors: Hilger Ralf Axel , Wegener Tobias , Richly Heike , Ludwig Georg , Mross Klaus , Scheulen Max E. 
Published: June 2012

Abstract
Introduction: TriN 2755 is a cytotoxic compound with a novel chemical structure, which carries a triazene group as cytotoxic principle. TriN 2755 demonstrated antitumor activity in human colon carcinoma, breast cancer and malignant melanoma models in nude mouse and rat. In contrast to 5-FU partial tumor remission was achieved in k-ras mutant colon xengrafts CXF158 and 280 without any signs of toxicity. Significant cytotoxic effects as well as prevention of metastasis formation and growth have also being observed in triazene-resistant MEXF276/1341 xenografts in addition to the B16F10 murine tumor mouse model. Methods: The phase I study is an ongoing dose-escalation trial investigating the safety and pharmacokinetic profile of two dose-schedules of TriN 2755 given intravenously either once every four weeks or once weekly until discontinuation due to toxicity or tumor progression. PK is assessed on day 1 and 2 of cycle 1. Tumor response is evaluated according to RECIST. Up to now, dose escalation for the first group of patients receiving treatment every four weeks was performed starting from 25 mg up to 4.000 mg flat dose according to an accelerated dose escalation scheme. Blood samples were collected prior to first dose, during the four hour continuous infusion (0.5h, 1.5h, and 3.5h after start of infusion), and 5, 15, 45 min, 1, 2, 4, 8, and 24 h after end of infusion, respectively. In addition, urine fractions were collected within 24 h after start of infusion. TriN 2755 was measured by using a validated RP-HPLC using UV detection in addition to mass spectrometric analysis; PK calculations were performed by using the program TOPFIT 2.0.
Results: In the dose range between 25 mg and 3.200 mg most frequent AEs were CTC grade 1-2 nausea and vomiting. No hematologic toxicity has been observed so far. In a dose range between 25 mg and 1.600 mg, the PK could be described by a linear model. Doubling the dose from 1.600 to 3.200 mg, AUC as well as Cmax increased more than 3fold, indicating a change to nonlinearity. This phenomenon was also obtained for the main metabolite M1 bearing the triazene group, thus to be considered as an active metabolite.
Conclusions: TriN 2755 was well tolerated when given at doses up to 3.200 mg once every four weeks. The toxicity evaluation with the 4.000 mg dose is ongoing with additional patients being enrolled. In two out of ten evaluable patients stable disease was observed for five months. After determination of the MTD in the ongoing schedule, further patients will be recruited for weekly treatment. Optimal dose and regimen will be determined for phase II trials.
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 1293. doi:10.1158/1538-7445.AM2011-1293