Phase 1 dose escalation study of AQ4N, a selective hypoxic cell cytotoxin, with fractionated radiotherapy (RT): First report.
Benghiat A., Steward WP., Loadman PM., Middleton M., Talbot D., Patterson LH., Ford S., Turner A.
2091 Background: Most solid tumours contain hypoxic cells which are relatively radioresistant. AQ4N is designed to be non toxic until selectively activated by bioreduction in hypoxic cells to AQ4, a highly potent, stable Topoisomerase II inhibitor. Animal in vivo models have shown enhancement of the effects of radiation by AQ4N, enabling a 50% reduction in the radiation dose for the same antitumour effect. Here we report the first Phase 1 study to determine the pharmacokinetics (PK) and toxicity of AQ4N in humans. METHODS: 13 patients with advanced esophageal carcinoma (7 adenocarcinoma and 6 Squamous carcinoma) suitable for palliative RT were recruited (ages 55-88 years, M 8, F 5). AQ4N was administered as a 30 min IV infusion on Days 1 and 14, with the first RT fraction given six hours after the second dose of AQ4N. The total RT dose was 20Gy in 5 daily fractions. Sequential plasma samples were taken on day 1. The dose was escalated from 22.5 to 246 mg /m(2). RESULTS: There were no drug related deaths. 1 patient died after the first AQ4N dose of a non drug related cause and is not evaluable. The most frequent adverse event was transient blue discolouration of the skin and urine. There were 8 other episodes, in 4 patients, of grade 3 or 4 toxicity possibly related to AQ4N; lymphocytopenia (n=2), fatigue (n=3), hyponatremia (n=3), hyperuricemia (n=1). None of these was clinically significant. PK studies showed a predictable dose related increase in AUC with mean clearance of 2.91 l h m(-2) (range 1.84-5.2) and a t 1/2 of 2.9h (range 2.4-5.1). Cmax at 246 mg/m(2) was 40.3ug ml(-1). A mean 48% of dose was excreted unchanged in the urine within 24 hrs, with metabolites representing <2% of parent compound. CONCLUSION: AQ4N is generally well tolerated with favourable PK, meriting further investigation. The MTD and DLT have not yet been reached with the RT doses used in this study. No additional normal tissue radiation related toxicity has been observed. (study supported by BTG International, UK) [Table: see text].