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2062 Background: AQ4N is activated in hypoxic cells to AQ4, a topoisomerase II inhibitor with radiosensitizing properties. This phase 1 study evaluated AQ4N and RT in patients (pts) with advanced esophageal cancer. METHODS: 22 pts (14 adenocarcinoma, 8 squamous carcinoma) suitable for palliative RT were studied (ages 55-88 years, M 16, F 6). AQ4N was given as a 30min iv infusion on days 1 and 14, with RT starting 6 hours after the second dose (20Gy in 5 daily fractions). The AQ4N dose was escalated from 22.5 to 447 mg /m(2) in sequential pt cohorts. In 3 pts (all receiving 447mg/m(2)), biopsies of tumour and normal esophageal tissue were taken 24 - 48 hours after the first dose and tissue concentrations of AQ4N and AQ4 measured using a sensitive LC/MS/MS technique. RESULTS: AQ4N was well tolerated, although pts developed transient generalised blue skin and urine discolouration. There were no drug related deaths. 1 pt was not evaluable. There were 16 episodes in 10 pts of grade 3 or 4 toxicity (probably drug related): lymphopenia (n=9), hyponatremia (n=3), fatigue (n=3) and hyperuricemia (n=1). None was clinically significant. PK studies showed a predictable dose related increase in AUC to a mean of 271+/- 127ug h ml(-1) at 447mg/m(2). This AUC is in excess of those seen in mice at therapeutic doses. A mean clearance of 2.54 l h m(-2) (range 1.59 - 5.2) and a t 1/2 of 4.3h (range 2.1 -10.6) were calculated. 57+/-23.8% of dose was excreted unchanged in the urine within 24 hrs. Calculated concentrations (ng ml(-1)) of AQ4 in tumour and normal tissue were 1744 and 295, 316 and <101, 585 and 265 respectively for three individual patients. In each case tumour tissue concentrations were greater than those in normal tissue with a mean ratio of >3.7 fold. Tumour concentrations of the active AQ4 are well above the IC50 values needed in vitro. CONCLUSION: AQ4N is well tolerated without serious toxicity. The DLT and MTD were not reached in this study, but a dose for future development was chosen before toxicity occurred using PK targeting and from a demonstration of the preferential conversion to AQ4 in tumour tissue. No excess normal tissue radiation related morbidity was observed. (Supported by BTG International, UK) [Table: see text].

Type

Journal article

Journal

J Clin Oncol

Publication Date

06/2005

Volume

23