A Phase I Dose Escalation Study on the Tolerability and Activity of TriN 2755 in Patients With Advanced Solid Tumors and Sarcomas Using Two Different Dosage Regimens

This is an open-label, parallel-group, two-center, safety, activity and pharmacokinetic study of TriN 2755 given at increasing dose levels as intravenous infusions administered over 4 hours. The study is divided into two parts: Part I a dose escalation phase and Part II an extension phase.

开始日期2009-11-01

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Trin Therapeutics GmbH

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2011-11-12·Molecular Cancer Therapeutics

Abstract C119: Depletion of O6-methylguanine DNA methyltransferase (MGMT) by TriN3001 leads to remission in SW-480 xenograft mice.

作者: Ramachandran, Balaji ; Ludwig, Georg ; Luetscher, Nina ; Wegener, Tobias ; Scheulen, Max Ernst ; Hilger, Ralf A.

AbstractBackground: TriN2755 is an alkylating agent currently under investigation in a phase-I study. Pharmacokinetic evaluation showed high inter-individual variability of the plasma concentration of its metabolite TriN3001. We speculate that differences in renal and metabolic clearance of TriN2755 and different expression of MGMT had contributed to the heterogeneous responses in xenograft models. We hypothesize that administration of TriN3001 improves predictability of drug levels and broadens the therapeutic window. In this study, we investigated the anti-tumor effect of TriN3001 given intraperitoneally after treatment of TriN2755 and temozolomide (TEM) in the colon-cancer cell line SW-480.Material and Methods: The in vitro effect of TriN2755 and 3001 on the proliferation of SW-480 was evaluated by IC50 determination. To study the in vivo efficacy, 5 × 106 cells of each cell line were inoculated in the flanks or back of nude mice. SW-480 mice were treated with TriN2755 (500mg/kg, biw, ip), TEM (120mg/kg qd×5, po) and NaCl as control. Treatment stopped at day 24 for interim-analysis. Mice were then being treated once daily with TriN3001 at a dose of 67,6mg/kg (low dose, former TriN), 100mg/kg (mid dose, former TEM) and 150mg/kg (high dose, former control) for another 16 to 20 days. Antitumor activity was assessed as (i) tumor volume inhibition relative to a vehicle control group for TriN2755 and (ii) change in tumor size from start of treatment for TriN3001. Tolerability was analysed by recording mortality, body weight loss and gross necropsy. Plasma and tissues were collected for pharmacokinetic and -dynamic evaluation.Results: In vitro, TriN2755 and 3001 and TEM displayed only weak growth inhibition with IC50 values of >3mM, 1mM and 1.2mM respectively. Nevertheless, in vivo T/C values of 40% (TriN2755) and 29% (TEM) were achieved at day 21. TEM and TriN2755 showed acceptable tolerability with no mortality and maximum body weight losses of 7% (TriN2755) and 10% (TEM). Daily administration of TriN3001 lead to remission in all mice, ranging from 66mm3 (30,3%) in the low, 77,6mm3 (23,1%) in the mid and 224mm3 (29,4%) in the high dose. TriN3001 and its metabolites were detectable in plasma and all tissues. In tumors, depletion of the repair enzyme MGMT increased over time with 60% depletion at 90min. Body weight loss didn't appear in the mid but in the low (−6%) and high (−20%) dose. At the end of treatment, thrombocytes and erythrocytes are within the reference range, lymphocytes lower and granulocytes higher than the reference.Conclusions: Daily application of TriN3001 led to remission of SW-480 tumors in mice independent from magnitude of tumor size. The treatment caused a marked depletion of MGMT protein in tumors. A second metabolite, with an IC50 value about 10fold lower than TriN3001 may have contributed to the efficacy. Further PK/PD data will be presented.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C119.

2011-04-15·Cancer Research

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)

作者: Scheulen, Max E. ; Richly, Heike ; Mross, Klaus ; Wegener, Tobias ; Hilger, Ralf Axel ; Ludwig, Georg

AbstractIntroduction: 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

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