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 journalArticle

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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.

LanguageEnglish
Pages1344-1348
Number of pages5
JournalJournal of Urology
Volume176
Issue number4
Early online date3 Sep 2006
DOIs
Publication statusPublished - Oct 2006
Externally publishedYes

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apaziquone
Urinary Bladder Neoplasms
Facilitative Glucose Transport Proteins
Transitional Cell Carcinoma
Urinary Bladder
Urine
Intravesical Administration
Dysuria
Hematuria
NADP
Intravenous Administration

Cite this

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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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.",
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.}",
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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 journalArticle

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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Puri R, Palit V, Loadman PM, Flannigan M, Shah T, Choudry GA et al. Phase I/II Pilot Study of Intravesical Apaziquone (EO9) for Superficial Bladder Cancer. Journal of Urology. 2006 Oct;176(4):1344-1348. https://doi.org/10.1016/j.juro.2006.06.047