The use of pharmacokinetic and pharmacodynamic endpoints to determine dose of AQ4N given with radiotherapy (RT).
Benghiat A., Steward WP., Middleton M., Talbot D., Patterson LH., Ford SJ., Hayward C., Loadman PM.
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].