SR4554 as a non-invasive probe of tumor hypoxia detected by Magnetic Resonance Spectroscopy: Update of a Phase I Trial

Abstract

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Introduction. SR4554 is a novel fluorinated 2-nitroimidazole which is reduced and bound in hypoxic cells. It was specifically designed for use as a non-invasive probe of tumor hypoxia detectable by in vivo ¹⁹F Magnetic Resonance Spectroscopy (MRS). Our earlier Phase I study of SR4554 showed a plasma T_1/2 of ∼ 3.9 hr, and a maximum tolerated dose of 1400mg/m² with nausea and vomiting being the dose-limiting toxicities. Surface coil-localised SR4554 signals were above the threshold for detection at 16 hours (5xT_1/2) post-infusion in 8/14 patients suggesting SR4554 retention indicative of tumor hypoxia. In this part of the study, we investigated co-administration of anti-emetics to permit higher doses of SR4554 and hence better quality data localized to the tumor. Methods. Eligibility criteria included tumors ≥ 3cm which were ≤ 4cm deep. Measurements were performed using a 1.5T Siemens Vision MR system, a 5, 10 or 16cm dual resonant ¹H/¹⁹F surface coil and pulse-acquire plus CSI-localized ¹⁹F MRS acquisition. SR4554 was administered at 1800mg/m² (intravenous, over 1 hour) with prophylactic metoclopramide (10mg, oral), and increased by 400mg/m² in subsequent patients to 2600mg/m². MRS#1 was acquired immediately after the infusion, MRS#2 was acquired at 12-16hr post-infusion to detect ¹⁹F signals indicative of tumor hypoxia following washout of parent SR4554 from tumor. Plasma and urine samples were obtained for pharmacokinetic (PK) studies. Results. Five patients with a variety of malignancy (Gastrointestinal Stromal Tumor, melanoma, gastric, and head & neck cancer) have been enrolled to date at these dose levels: 1800mg/m² (n=1), 2200mg/m² (n=1), 2600mg/m² (n=3). Median age: 53. ECOG Performance Status: 1. SR4554 was well tolerated overall. Toxicities included Grade 1 nausea and vomiting (n=1) and Grade 1 headache (n=4). PK studies of SR4554 at 1800mg/m², 2200mg/m², 2600mg/m² respectively showed: mean C_max (mg/L): 73.7, 85.1, 159.1; mean T_1/2 (hr): 3.1, 3.2, 4.2; mean clearance (L/hr): 12.8, 12.7, 8.8. SR4554 signals were seen on MRS#1 in all 5 patients. Localized studies at 12hr showed ¹⁹F signals above detection threshold in 1/2 patients (at 2600mg/m² of SR4554), but not in 3/3 patients who had MRS#2 at 16hr. Conclusion. This part of the study has demonstrated the feasibility of administering higher doses of SR4554 with prophylactic anti-emetics. This study is on-going and further patients will receive 2600mg/m² of SR4554.