Phase II study of intravesical therapy with AD32 in patients with papillary urothelial carcinoma or carcinoma in situ (CIS) refractory to prior therapy with bacillus Calmette-Guerin (E3897): A trial of the Eastern Cooperative Oncology Group

Abstract

SUMMARYObjectives-Assess the safety and effectiveness of AD32, a doxorubicin analogue with little systemic exposure when administered intravesically, in patients with recurrent or refractory superficial urothelial carcinoma (formerly called transitional cell carcinoma [TCC]), or carcinoma in situ (CIS), who have failed prior BCG-based immunotherapy.Methods-Eligible patients received 6 weekly doses (800mg) of intravesical AD32 and were evaluated at 12-week intervals for 24 months or until date of worsening disease. Primary analysis was the proportion of all patients recurrence-free at 12 months. Treatment-related and GU-specific toxicities were also examined. All participating institutions submitted the protocol for Institutional Review Board (IRB) approval.Results-The study was halted due to unavailability of study drug after accrual of 48 of a planned 64 patients; 42 were included in the analysis. Of these, 28 (67%) were still alive after median followup of 61.1 months. Of 21 TCC patients, 18 (85.7%) experienced disease recurrence (median time to recurrence, 5.3 months). Of the 5 CIS patients with complete response (CR), 3 (60%) experienced disease recurrence; (median time to recurrence, 37.3 months). Recurrence-free rates at 12 and 24 months were 20% (90% CI, 7.8%, 36.1%) and 15% (90 CI, 4.9%, 30.2%), respectively, for patients with TCC and 80% (90% CI, 31.4%, 95.8%) at both intervals for CIS patients with CR. Infection was the most common treatment-related toxicity; no grade 4 or higher toxicity was observed. The most common GU-specific toxicity was increased frequency/urgency.Conclusions-AD32 is safe and active for treatment of recurrent or refractory superficial bladder carcinoma. The agent awaits more complete characterization when drug production problems can be solved.

Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder

“…The results of this first study on the clinical, real-world use of valrubicin since its reintroduction to the market in 2009 are consistent with data from previous, prospective studies demonstrating the effectiveness and safety for treating NMIBC, including CIS, in patients who are not undergoing immediate cystectomy [Dinney et al 2013; Greenberg et al 1997; Ignatoff et al 2009]. As expected in an NMIBC population, the patient population was heavily pretreated, of advanced age, and had significant comorbid burden, including some conditions that were contraindications to surgery.…”

“…For select patients with CIS, valrubicin was previously shown to be an effective, well-tolerated option before considering cystectomy, which may have a negative impact on patient quality of life, morbidity, and mortality [Clark et al 2005; Dinney et al 2013; Greenberg et al 1997; Ignatoff et al 2009]. Medical records data from the current study provide a good description of the impact of interventions in actual clinical practice, are also relevant for decision making, and complement data derived within the artificial constructs of a clinical trial.…”

“…Several other trials have provided supportive evidence of safety and effectiveness [Blum et al 1981;Dinney et al 2013;Greenberg et al 1997;Ignatoff et al 2009;Patterson et al 2000]. A post-hoc analysis from the pivotal trial showed that the effectiveness of valrubicin was similar regardless of patient age, sex, smoking status, duration of bladder cancer, baseline urinary symptoms, and history of prior NMIBC therapies [Steinberg et al 2011].…”

“…Valrubicin was approved in the USA in 1998, based on data from a pivotal phase III study [Steinberg et al 2000], for use in patients with BCG-refractory carcinoma in situ (CIS) when cystectomy is not an option because of morbidity and mortality [Montie et al 2011; Endo Pharmaceuticals, 2011]. Several other trials have provided supportive evidence of safety and effectiveness [Blum et al 1981; Dinney et al 2013; Greenberg et al 1997; Ignatoff et al 2009; Patterson et al 2000]. A post-hoc analysis from the pivotal trial showed that the effectiveness of valrubicin was similar regardless of patient age, sex, smoking status, duration of bladder cancer, baseline urinary symptoms, and history of prior NMIBC therapies [Steinberg et al 2011].…”

Novel intravesical therapeutics in the treatment of non-muscle invasive bladder cancer: Horizon scanning

“…The median time to treatment failure was almost 18 months (74). Further clinical studies of intravesical valrubicin have found similar treatment response rates (73, [75][76][77][78].…”