A phase i study of the nitroimidazole hypoxia marker SR4554 using 19 F magnetic resonance spectroscopy

Abstract

Background:SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19 F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m 2 was established as MTD. Preliminary MRS studies demonstrated some evidence of 19 F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19 F MRS signal.Methods:Patients had tumours 3 cm in diameter and 4 cm deep. Measurements were performed using 1 H/ 19 F surface coils and localised 19 F MRS acquisition. SR4554 was administered at 1400 mg m 2, with subsequent increase to 2600 mg m 2 using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19 Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)100.Results:A total of 26 patients enrolled at: 1400 (n16), 1800 (n1), 2200 (n1) and 2600 mg m 2 (n8). SR4554 was well tolerated and toxicities were all grade 1; mean plasma elimination half-life was 3.70.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19 F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6-43.7) compared with 4.1 (range 0.6-7.3) for plasma samples taken at the same times (P0.001) suggesting 19 F retention in tumour and, therefore, the presence of hypoxia.Conclusion:We have demonstrated the feasibility of using 19 F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19 F retention in tumour, supporting further development of this technique for detection of tumour hypoxia. © 2009 Cancer Research UK.