Immunostimulation in the urinary bladder by local application ofNocardia rubra cell wall skeleton preparation (Rubratin) for superficial bladder cancer immunotherapy — a phase I/II study

Purpose Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. Patients and Methods This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. Results Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. Conclusion Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

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PHASE I PHARMACOKINETIC STUDY OF A SINGLE INTRAVESICAL INSTILLATION OF GEMCITABINE ADMINISTERED IMMEDIATELY AFTER TRANSURETHRAL RESECTION PLUS MULTIPLE RANDOM BIOPSIES IN PATIENTS WITH SUPERFICIAL BLADDER CANCER

The Journal of Urology ◽

10.1097/01.ju.0000131770.14409.7f ◽

2004 ◽

Vol 172 (2) ◽

pp. 485-488 ◽

Cited By ~ 26

Author(s):

JUAN PALOU ◽

ANTONIO CARCAS ◽

JOSE SEGARRA ◽

BLANCA DUQUE ◽

JOSE SALVADOR ◽

...

Keyword(s):

Bladder Cancer ◽

Phase I ◽

Pharmacokinetic Study ◽

Transurethral Resection ◽

Superficial Bladder Cancer ◽

Intravesical Instillation

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A phase I study of intravesical Ad-IFN in superficial bladder cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16048 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16048-e16048

Author(s):

C. P. Dinney ◽

W. F. Benedict ◽

D. L. Cutler ◽

M. F. Fisher ◽

M. A. O'Donnell

Keyword(s):

Bladder Cancer ◽

Phase I ◽

Phase I Study ◽

Prolonged Exposure ◽

Superficial Bladder Cancer ◽

Response Duration ◽

Maximum Tolerated Dose ◽

Interferon Α ◽

Anticholinergic Medication ◽

Open Label

e16048 Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×109, 1×1010, 3x1010, 1×1011, or 3×1011 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development. [Table: see text]

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