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

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

doi:10.1016/j.juro.2006.06.047

Cited by 36 publications

(33 citation statements)

References 17 publications

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“…Furthermore, the predominant metabolite found in blood and urine following intravenous administration was the inactive, aziridine ring open metabolite EO5A [54,59]. Following intravesical administration, two clinical studies have investigated the pharmacokinetic and safety of apaziquone [60,61]. In the first of these studies [61], apaziquone was administered 2 weeks after TURBT and for the first six patients entered into the trial, each received an escalating dose of apaziquone with one dose per week (for a total of 6 weeks).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

“…Following intravesical administration, two clinical studies have investigated the pharmacokinetic and safety of apaziquone [60,61]. In the first of these studies [61], apaziquone was administered 2 weeks after TURBT and for the first six patients entered into the trial, each received an escalating dose of apaziquone with one dose per week (for a total of 6 weeks). At all doses administered, no detectable levels of apaziquone or EO5A were found in the blood.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

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Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Phillips

Hendriks²,

Sweeney

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Apaziquone (also known as EO9 and Qapzola TM ) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers. ARTICLE HISTORY

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Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Phillips

Hendriks²,

Sweeney

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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“…As for porfiromycin, preclinical data supported the clinical development of E09, but the clinical utility of the agent appeared compromised by very poor biodistribution and pharmacokinetics 312 . However, E09 has had a recent clinical revival in superficial bladder cancer where intravesical administration circumvents the delivery and clearance issues 313,314 . Development of the nitroimidazoles progressed with the 2-nitroimidazole RSU1069: a modified misonidazole derivative that acts as a bi-functional alkylating agent by virtue of an aziridine ring 315 .…”

Section: Prototype Agents In the Development Of Bioreductive Drugsmentioning

confidence: 99%

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Ebbesen

Pettersen

Gorr

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

176

118

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“…109 The relative stability of the compound and rapid pharmacokinetic elimination of the drug make it an intriguing agent for use in NMIBC, and Phase I/II trials have confirmed minimal local and systemic toxicity. 9,110,111 In a recent update of their Phase I study, Jain et al reported that of the eight patients who achieved a complete response, 50% relapsed over a median follow-up of 31 months. Of note, the recurrence-free interval significantly increased following apaziquone administration compared with historic recurrence intervals pretreatment.…”

Section: Apaziquonementioning

confidence: 99%

Emerging intravesical therapies for management of nonmuscle invasive bladder cancer

Smaldone¹,

Tomaszewski²

2010

OAJU

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Transitional cell carcinoma (TCC) is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer (NMIBC). Intravesical bacillus Calmette-Guerin (BCG) is the most effective agent for preventing disease recurrence, and the only therapy able to inhibit disease progression. However, recurrence rates as high as 30% and significant local and systemic toxicity have led to increased interest in alternative intravesical therapies. In patients refractory or intolerant to BCG, BCG-interferon α2b, gemcitabine, and anthracyclines (doxorubicin, epirubicin, valrubicin) have demonstrated durable clinical responses. Phase I trials investigating alternative cytotoxic agents, such as apaziquone, taxanes (docetaxel, paclitaxel), and suramin are reporting promising data. Novel immunomodulating agents have demonstrated promise as efficacious alternatives in patients refractory to BCG. Optimization of existing chemotherapeutic regimens using hyperthermia, photodynamic therapy, magnetically-targeted carriers, and liposomes remains an area of active investigation. Despite enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and selected patients with naïve T1 tumors and aggressive features. This report provides a comprehensive review of contemporary intravesical therapy for NMIBC and refractory NMIBC, with an emphasis on emerging agents and novel treatment modalities.

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

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Cited by 36 publications

References 17 publications

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer

Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Emerging intravesical therapies for management of nonmuscle invasive bladder cancer

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