EOquin (formerly known as EO9) is an indolequinone bioreductive drug which despite showing promising preclinical activity, failed to show efficacy in phase II clinical trials. Poor drug delivery to tumours as a result of a combination of rapid pharmacokinetic elimination and relatively poor penetration through avascular tissue has been suggested as the principle reason for EOquin’s lack of clinical efficacy to date (Phillips et al, Br J Cancer 77; 2112-2119, 1998). The rational for this study is that intravesical administration of EOquin would circumvent the drug delivery problem and any drug reaching the blood stream would be rapidly cleared thereby reducing the risk of systemic toxicity. The objectives of this study were to determine the safe dose of EOquin and to gain evidence of efficacy. Twelve patients entered the study, all of which had received prior chemo or immunotherapy and had recurrent low grade (G1/G2) multiple superficial (Ta/T1) bladder tumours. All but one lesion was surgically removed with the remaining tumour serving as a marker lesion to assess EOquin efficacy. Patients were split into two cohorts (6 in each group). The first cohort received escalating doses of EOquin administered intravesically on a weekly schedule for 6 weeks, starting at 0.5 mg/40ml and doubled until toxicity or the maximum dose of 16 mg/40ml was achieved. The second cohort received a 6 week course of EOquin at a ‘safe’ dose established in the first cohort. In the dose escalation cohort, all patients tolerated 4 mg/40ml. Two patients experienced local toxicity at 8 mg/40ml (dysuria and haematouria grades 2 and 3) and the subsequent dose was reduced to 4 mg/40ml which was well tolerated. Four patients received the maximun dose of 16 mg/40ml, two of which experienced mild dysuria and haematouria whereas the remaining two patients tolerated EOquin at 16 mg/40ml. A dose of 4 mg/40ml was selected for the second cohort of patients and this was well tolerated with no local toxicity reported. No systemic side effects were observed in all cases and EOquin could not be detected in the plasma during and at the end of the instillation. In the urine collected at the end of the one hour instillation, concentrations of EOquin were linear and dose dependent. Two weeks after the last instillation, the effect of EOquin against the marker lesion was determined by cystoscopy and microscopic examination of biopsies. 8 out of the 12 complete responses were obtained. Follow up times range from 8 to 24 months and one patient’s tumour has recurred (18 months after treatment). No other recurrences have been reported (2 patients remain disease free 24 months after treatment). These interim results suggest that intravesical EOquin has activity against superficial bladder cancer and early indications suggest that response is durable. A multi-centre phase II study of intravesical EOquin against superficial bladder cancer is underway.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]