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A Phase I Study of SR-4554 via Intravenous Administration for Noninvasive Investigation of Tumor Hypoxia by Magnetic Resonance Spectroscopy in Patients with Malignancy

Cancer Research UK Centre for Cancer Therapeutics [B. M. S., L. S., R. R., R. G., S. T., F. R., I. J., P. W.] and Cancer Research UK Clinical Magnetic Resonance Research Group [G. S. P., M. O. L.], Institute of Cancer Research, Sutton, Surrey; Royal Marsden Hospital, Sutton, Surrey [G. S. P., M. O. L., I. J.]; Drug Development Office, Cancer Research UK, London [A. T.]; and Cancer Research UK Phase I/II Trials Committee Formulation Unit, University of Strathclyde [G. H.], Glasgow, United Kingdom

ABSTRACT

Purpose: To perform a Phase I study of SR-4554, a fluorinated 2-nitroimidazole noninvasive probe of tumor hypoxia detected by ¹⁹F magnetic resonance spectroscopy (MRS).

Experimental Design: SR-4554 administration, on days 1 and 8, was followed by plasma sampling for pharmacokinetic studies and by three MRS studies performed over 24 h on days 8 and 9. Unlocalized MR spectra were acquired from tumor (10- or 16-cm dual resonant ¹H/¹⁹F surface coil; 1.5 T Siemens Vision MR system; 2048 transients acquired over 34 min; 1.28-ms adiabatic pulse; repetition time, 1 s). Plasma drug concentrations were measured with a validated high-performance liquid chromatography method. Noncompartmental pharmacokinetic analysis was performed.

Results: Eight patients underwent pharmacokinetic studies, receiving doses of SR-4554 of 400-1600 mg/m². Peak plasma concentrations increased linearly with the SR-4554 dose (r² = 0.80; P = 0.0002). The plasma elimination half-life was relatively short (mean ± SD, 3.28 ± 0.59 h), and plasma clearance was quite rapid (mean ± SD, 12.8 ± 3.3 liters/h). Urinary recovery was generally high. SR-4554 was well tolerated. A single patient experienced dose-limiting toxicity (nausea and vomiting) at 1600 mg/m². The maximum tolerated dose was 1400 mg/m². SR-4554 was detected spectroscopically in tumors immediately after infusion at doses of 400-1600 mg/m². At the highest dose (1600 mg/m²), SR-4554 was detectable in tumor at 8 h, but not at 27 h.

Conclusions: SR-4554 has plasma pharmacokinetic and toxicity profiles suitable for use as a hypoxia probe. It can be detected in tumors by unlocalized MRS. Additional clinical studies are warranted.

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