Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder

Steinberg, Gary D.; Bahnson, Robert R.; Brosman, Stanley A.; Middleton, Richard; Wajsman, Zev; Wehle, Michael J.

doi:10.1016/s0022-5347(05)67799-3

Cited by 298 publications

(135 citation statements)

References 14 publications

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“…Consequently, in 2013, Dinney et al provided an updated report on the safety and efficacy of valrubicin based on the revised phase III trial data along with data from a supportive phase II/III trial (A9303 trial). Based on the updates to the data originally reported in Steinberg, et al, 153 the complete response rate changed from 21% to 18%, which is identical to the CR reported in the supportive A9303 trial by Dinney et al 154 The supportive trial also demonstrated a disease-free status of 22% at six months, 10% at one year, and 4% at two years. 154 Because patients in the A9303 trial were less highly treated than in the previous phase III trial, Dinney et al conclude that valrubicin is both safe and efficacious in highly pretreated populations as well as those with few previous therapies.…”

Section: Current State Of the Fieldsupporting

confidence: 62%

“…Findings demonstrated that six weekly instillations of 800mg of valrubicin was well-tolerated and that 21% of patients remained disease-free six months after treatment, and responses were durable, with a median response time greater than 18 months. 153 These data were subsequently revised but only reported in the FDA prescribing information. Consequently, in 2013, Dinney et al provided an updated report on the safety and efficacy of valrubicin based on the revised phase III trial data along with data from a supportive phase II/III trial (A9303 trial).…”

Section: Current State Of the Fieldmentioning

confidence: 99%

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Molecular cancer prevention: Current status and future directions

Maresso

Tsai

Brown

et al. 2015

CA A Cancer J Clinicians

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The heterogeneity and complexity of advanced cancers strongly supports the rationale for an enhanced focus on molecular prevention as a priority strategy to reduce the burden of cancer. Molecular prevention encompasses traditional chemopreventive agents as well as vaccinations and therapeutic approaches to cancer-predisposing conditions. Despite challenges to the field, we now have refined insights into cancer etiology and early pathogenesis; successful risk assessment and new risk models; agents with broad preventive efficacy (e.g., aspirin) in common chronic diseases, including cancer; and a successful track record of more than 10 agents approved by the FDA for the treatment of precancerous lesions or cancer risk reduction. The development of molecular preventive agents does not differ significantly from the development of therapies for advanced cancers, yet has unique challenges and special considerations given that it most often involves healthy or asymptomatic individuals. Agents, biomarkers, cohorts, overall design, and endpoints are key determinants of molecular preventive trials, as with therapeutic trials, although distinctions exist for each within the preventive setting. Progress in the development and evolution of molecular preventive agents has been steadier in some organ systems, such as breast and skin, than in others. In order for molecular prevention to be fully realized as an effective strategy, a number of challenges to the field must be addressed. Here we provide a brief overview of the context for and special considerations of molecular prevention along with a discussion of the results of major randomized controlled trials.

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Section: Current State Of the Fieldsupporting

confidence: 62%

Section: Current State Of the Fieldmentioning

confidence: 99%

Molecular cancer prevention: Current status and future directions

Maresso

Tsai

Brown

et al. 2015

CA A Cancer J Clinicians

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“…For post-BCG tumor recurrences, BCG-unresponsive disease is defined by any of the following features: recurrent NMIUC after 2 prior adequate BCG regimens, recurrent T1 disease at the initial 3-month post-treatment TURBT, recurrent NMIUC within 6 months of last BCG administration, and NMIUC involving the prostatic urethra (8). Transient remissions are often observed with additional intravesical therapy approaches, however, only 10-15% of patients remain recurrence-free at 1 year (9, 10). Thus, cystectomy is considered a standard treatment in BCG-unresponsive patients (11).…”

Section: Introductionmentioning

confidence: 99%

A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157

Hahn

Bivalacqua

Ross

et al. 2017

Clinical Cancer Research

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Purpose To assess the clinical and pharmacodynamic activity of dovitinib in a treatment resistant, molecularly enriched NMIUC population. Experimental Design A multi-site pilot phase 2 trial was conducted. Key eligibility criteria included: BCG unresponsive NMIUC (≥ 2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on / 2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate. Results Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut−, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included: median age 70 years; 85% male; CIS (3 pts), Ta/T1 (8 pts), and Ta/T1 + CIS (2 pts); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3-4 event. 6-month CR rate was 8% (0% in IHC+ Mut−; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94-5812 nM) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment. Conclusions Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in NMIUC patients. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in UC.

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“…This poses a serious dilemma, especially in those who refuse radical cystectomy or have too many comorbidities to undergo a major operation. While other therapies such as mitomycin C are considered in this unique setting, the only Food and Drug Administration (FDA) approved intravesical option for BCG “failure” is valrubicin, which exhibits a modest response rate of 21% at 6 months [10]. …”

Section: Introductionmentioning

confidence: 99%

Lenalidomide augments the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in vivo

Jinesh

Lee

Tran

et al. 2013

Urologic Oncology: Seminars and Original Investigations

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Objective Intravesical bacillus Calmette-Guerin (BCG) is the gold standard for high-grade non-muscle-invasive bladder cancer (NMIBC); however, some patients do not respond to initial therapy while others relapse and/or progress. Therefore, combination strategies that can enhance the efficacy and sustainability of BCG are needed. Herein, we explore the efficacy of lenalidomide, a thalidomide derivative with immunomodulatory effects, in combination with BCG, both in vitro and in vivo. Materials and methods We explored the outcomes of lenalidomide in combination with BCG in vivo using the MBT-2 cell line implanted in C3H immunocompetent mice. Apoptosis, cell proliferation, and microvessel density were measured by immunohistochemistry. In vitro, we performed Western blotting for cell cycle and apoptosis regulatory proteins and a chromatin condensation assay to evaluate TNF-α and FasL in combination with lenalidomide. Results In the mouse model, combination therapy with BCG and lenalidomide resulted in a statistically significant decrease in tumor size compared with the control group. IHC demonstrated a nonsignificant increase in apoptosis in the combination condition and no effect on cellular proliferation. Microvessel density was decreased in all treated conditions. In vitro, caspase-3 activation and chromatin condensation studies demonstrated increased cell death in the combinations of lenalidomide and TNF-α. Conclusions The immunomodulatory molecule lenalidomide augments the response to BCG in an in vivo mouse model. This provides the rationale for studying the combination in patients with high grade NMIBC.

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Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder

Abstract: Valrubicin was effective and well tolerated in patients with carcinoma in situ of the bladder refractory to BCG therapy. Delaying cystectomy while attempting salvage therapy with valrubicin does not pose an undue risk to most patients.

Cited by 298 publications

References 14 publications

Molecular cancer prevention: Current status and future directions

Molecular cancer prevention: Current status and future directions

A Phase II Trial of Dovitinib in BCG-Unresponsive Urothelial Carcinoma with FGFR3 Mutations or Overexpression: Hoosier Cancer Research Network Trial HCRN 12-157

Lenalidomide augments the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in vivo

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