Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer

Rajiv Puri; Victor Palit; Paul M. Loadman; Michael Flannigan; Tariq Shah; Guzanfar A. Choudry; Saurajyoti Basu; John A. Double; Gino Lenaz; Shanta Chawla; Mario Beer; Coen Van Kalken; Richard de Boer; Jos H. Beijnen; Christopher J. Twelves; Roger M. Phillips

doi:10.1016/j.juro.2006.06.047

Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer

Rajiv Puri, Victor Palit, Paul M. Loadman, Michael Flannigan, Tariq Shah, Guzanfar A. Choudry, Saurajyoti Basu, John A. Double, Gino Lenaz, Shanta Chawla, Mario Beer, Coen Van Kalken, Richard de Boer, Jos H. Beijnen, Christopher J. Twelves, Roger M. Phillips

Research output: Contribution to journal › Article

36 Citations (Scopus)

Abstract

Purpose: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma.

Materials and Methods: Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquin™ (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion.

Results: Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established.

Conclusions: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.

Original language	English
Pages (from-to)	1344-1348
Number of pages	5
Journal	Journal of Urology
Volume	176
Issue number	4
Early online date	3 Sep 2006
DOIs	https://doi.org/10.1016/j.juro.2006.06.047
Publication status	Published - Oct 2006
Externally published	Yes

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Puri, R., Palit, V., Loadman, P. M., Flannigan, M., Shah, T., Choudry, G. A., Basu, S., Double, J. A., Lenaz, G., Chawla, S., Beer, M., Van Kalken, C., de Boer, R., Beijnen, J. H., Twelves, C. J., & Phillips, R. M. (2006). Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer. Journal of Urology, 176(4), 1344-1348. https://doi.org/10.1016/j.juro.2006.06.047

Puri, Rajiv ; Palit, Victor ; Loadman, Paul M. ; Flannigan, Michael ; Shah, Tariq ; Choudry, Guzanfar A. ; Basu, Saurajyoti ; Double, John A. ; Lenaz, Gino ; Chawla, Shanta ; Beer, Mario ; Van Kalken, Coen ; de Boer, Richard ; Beijnen, Jos H. ; Twelves, Christopher J. ; Phillips, Roger M. / Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer. In: Journal of Urology. 2006 ; Vol. 176, No. 4. pp. 1344-1348.

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title = "Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer",

abstract = "Purpose: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma. Materials and Methods: Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquin{\texttrademark} (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion. Results: Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established. Conclusions: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.",

keywords = "bladder, bladder neoplasms, carcinoma, EO9, transitional cell",

author = "Rajiv Puri and Victor Palit and Loadman, {Paul M.} and Michael Flannigan and Tariq Shah and Choudry, {Guzanfar A.} and Saurajyoti Basu and Double, {John A.} and Gino Lenaz and Shanta Chawla and Mario Beer and {Van Kalken}, Coen and {de Boer}, Richard and Beijnen, {Jos H.} and Twelves, {Christopher J.} and Phillips, {Roger M.}",

year = "2006",

month = oct,

doi = "10.1016/j.juro.2006.06.047",

language = "English",

volume = "176",

pages = "1344--1348",

journal = "Journal of Urology",

issn = "0022-5347",

publisher = "Elsevier Inc.",

number = "4",

}

Puri, R, Palit, V, Loadman, PM, Flannigan, M, Shah, T, Choudry, GA, Basu, S, Double, JA, Lenaz, G, Chawla, S, Beer, M, Van Kalken, C, de Boer, R, Beijnen, JH, Twelves, CJ & Phillips, RM 2006, 'Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer', Journal of Urology, vol. 176, no. 4, pp. 1344-1348. https://doi.org/10.1016/j.juro.2006.06.047

Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer. / Puri, Rajiv; Palit, Victor; Loadman, Paul M.; Flannigan, Michael; Shah, Tariq; Choudry, Guzanfar A.; Basu, Saurajyoti; Double, John A.; Lenaz, Gino; Chawla, Shanta; Beer, Mario; Van Kalken, Coen; de Boer, Richard; Beijnen, Jos H.; Twelves, Christopher J.; Phillips, Roger M.

In: Journal of Urology, Vol. 176, No. 4, 10.2006, p. 1344-1348.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer

AU - Puri, Rajiv

AU - Palit, Victor

AU - Loadman, Paul M.

AU - Flannigan, Michael

AU - Shah, Tariq

AU - Choudry, Guzanfar A.

AU - Basu, Saurajyoti

AU - Double, John A.

AU - Lenaz, Gino

AU - Chawla, Shanta

AU - Beer, Mario

AU - Van Kalken, Coen

AU - de Boer, Richard

AU - Beijnen, Jos H.

AU - Twelves, Christopher J.

AU - Phillips, Roger M.

PY - 2006/10

Y1 - 2006/10

N2 - Purpose: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma. Materials and Methods: Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquin™ (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion. Results: Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established. Conclusions: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.

AB - Purpose: The quinone based bioreductive drug apaziquone (EO9) failed to demonstrate efficacy in previous phase II studies following intravenous administration. We determined the dose of apaziquone that can be safely administered intravesically and explored its activity for superficial bladder transitional cell carcinoma. Materials and Methods: Six patients with multifocal, Ta/T1 and G1/G2 transitional cell carcinoma of the bladder received escalating doses of apaziquone formulated as EOquin™ (0.5 mg/40 ml up to 16 mg/40 ml) weekly for 6 weeks. A further 6 patients received weekly apaziquone at the highest nontoxic dose established. Pharmacokinetic parameters were determined in urine and blood, and the pharmacodynamic markers NQO1 (reduced nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase-1) and glucose transporter 1 were also characterized. Efficacy was determined against a marker lesion. Results: Local toxicity (grades 2 and 3 dysuria, and hematuria) was observed at doses of 8 mg/40 ml and above but 4 mg/40 ml was well tolerated with no systemic or local side effects. Apaziquone in urine increased linearly with the dose but no apaziquone was detected in plasma. In 8 of 12 patients complete macroscopic and histological disappearance of the marker lesion occurred. A correlation between response and NQO1 and/or glucose transporter 1 expression could not be established. Conclusions: Intravesical administration of 4 mg/40 ml apaziquone was well tolerated and had ablative activity against superficial bladder cancer marker lesions.

KW - bladder

KW - bladder neoplasms

KW - carcinoma

KW - EO9

KW - transitional cell

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