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Definitions

• Non-muscle-invasive bladder cancer represents the most common disease state for patients with newly diagnosed bladder cancer. Those with high-grade (HG) tumors are at significant risk for both recurrence and progression.
• Bacillus Calmette-Guerin (BCG) represents the current preferred management. Nonetheless, approximately 30% of patients will not respond to BCG; among those who demonstrate an initial response, more than 50% will experience recurrence and progression during long-term follow-up.
• Valrubicin Valstar; Endo Pharmaceuticals, Malvern, Pa.
• Valrubicin the only agent currently approved by the FDA for the treatment of BCG-refractory CIS, provided a complete response rate of 18% at 6 months and a 1-year disease-free survival rate of approximately 10%.
• Promising results from early-phase trials have been reported for intravesical taxane and gemcitabine.
• Joudi et al. reported the final results from a national multicenter phase II trial of BCG plus IFN ⁇ -2b and noted that 45% of patients with BCG failure were free from recurrence at 2 years.
• IFN ⁇ -2b Intravesical interferon alfa-2b protein
• Intron A Merck, Kenilworth, N.J.
• Intravesical IFN ⁇ -2b gene delivery offers a novel approach and increases the duration of exposure to IFN ⁇ -2b.
• Recombinant adenovirus (rAd)-IFN ⁇ -2b is a replication-deficient adenovirus-based gene transfer vector that encodes the human IFN ⁇ -2b gene.
• Syn3 a polyamide surfactant, is incorporated into the drug formulation (ADSTILADRIN® rAd-IFN ⁇ /Syn3TM, FKD Therapies Oy, Kuopio, Finland) to enhance adenoviral transduction of the bladder lining.
• Dramatic enrichment of rAd-IFN ⁇ gene transfer and expression has been shown with Syn3TM in both normal urothelium and human urothelial carcinoma that grows in mice.
• rAd-IFN ⁇ -2b gene therapy mimics the physiologic events associated with viral infection, which results in local rather than systemic IFN ⁇ -2b production and subsequent tumor regression.
• the excipient Syn3 is a polyamide surfactant that enhances adenoviral gene transfer to the bladder epithelium. Dose-dependent adenoviral gene transfer and urine concentrations of IFN ⁇ -2b were confirmed. Of 14 patients treated with dose levels of rAd-IFN ⁇ /Syn3® that resulted in measurable urine IFN ⁇ , six (43%) were free from recurrence at 3 months and had no dose-limiting toxicity, and two patients remained disease free at 29 and 39 months.
• BCG-refractory disease was defined as the inability to achieve a disease-free state at 6 months after adequate induction BCG therapy with either maintenance or reinduction at 3 months. “Adequate induction” was defined as a minimum of five of six treatments, and “adequate maintenance” was defined as a minimum of two of three treatments. BCG relapse was defined as recurrence within 1 year after a complete response to adequate BCG treatment (at least five and two instillations). Patients were required to have undergone visually complete resection of papillary lesions by transurethral resection of bladder tumors. Patients could not have received intravesical therapy within 3 months before beginning study treatment, with the exception of cytotoxic agents when administered as a single instillation immediately after a transurethral resection. All participants who entered the study provided written or oral informed consent.
• Patients were assigned by computer-generated random assignment, with a constrained 1:1 sequence, to receive either low-dose (1 ⁇ 1011 viral particles [vp]/mL) or high-dose (3 ⁇ 1011 vp/mL) rAd-IFN ⁇ /Syn3. These doses were the most promising observed in the phase I study.
• the total doses administered were 7.5 ⁇ 1012 vp in the low-dose group and 2.25 ⁇ 1013 vp in the high-dose group.
• Treatment allocation was performed centrally with a block size of two for all patients who had successfully completed screening, with the constraint that the first four patients at each site were balanced between cohorts.
• rAd-IFN ⁇ /Syn3TM in 75 mL was administered intravesically through a urethral catheter, with a planned retention time of 1 hour; an anti-cholinergic treatment was allowed to relieve urinary urgency and permit adequate retention.
• Patients without recurrence of HG disease at months 3, 6, and 9, as evaluated by cytology, cystoscopy, and biopsy (if clinically indicated) were then retreated at months 4, 7, and 10.
• a final efficacy evaluation was performed. This evaluation included a protocol-mandated biopsy from the site of the index tumor and at least five random biopsies, including the bladder dome, trigone, right and left lateral wall, posterior wall, and prostatic urethra in men with positive cytology or prior disease in this region.
• the primary end point was freedom from HG disease recurrence at 12 months, defined by a negative for cause or end of study biopsy. Secondary end points included response to treatment, defined as no evidence of recurrence of HG disease at 3, 6, and 9 months; incidence and time to cystectomy; and concentration of IFN ⁇ -2b in the urine.
• Safety assessments included physical examination, monitoring of vital signs, ECG, and standard clinical chemistry, hematology, and urinalysis assessments (performed by local laboratories). Safety end points include type, incidence, relatedness, and severity of AEs and severe ( ⁇ grade 3) AEs (SAES), as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).
• BCG bacillus Calmette-Guerin
• CIS carcinoma in situ
• ECOP PS Eastern Cooperative Oncology Group performance status
• IQR interquartile range
• rAd-IFN ⁇ /Syn3, recombinant adenovirus interferon alpha protein/Syn3 a nonreplicating recombinant adenovirus gene transfer vector for patients with high-grade BCG-refractory or relapsed non-muscle-invasive bladder cancer
• Ta papillary urothelial carcinoma confined to the mucosa
• HG RFS rate was comparable between the two dose groups, with 33.3% of patients (7 of 21; 90% CI, 16.8 to 53.6) in the low-dose group and 36.8% (7 of 19; CI, 18.8 to 58.2) in the high-dose group alive and free of HG disease at 12 months.
• 35.0% of patients (14 of 40; 90% CI, 22.6% to 49.2%) remained free of HG recurrence at 12 months after the initiation of rAd-IFN ⁇ /Syn3 treatment.
• Off-schedule disease assessments did not affect findings (Appendix, online only).
• the median time to HG recurrence or death was 6.5 months (90% CI, 3.52 to 12.78 months); the median time to HG recurrence was 3.52 months (90% CI, 3.02 to 12.78 months) for the low-dose group and was 11.73 months (90% CI, 5.88 months to not evaluable) for the high-dose group.
• HG RFS rates were broadly similar for men and women, for younger and older patients, for refractory or relapsed NMIBC, for CIS only or papillary tumors and CIS, and for patients with Ta and T1 disease only.
• HG RFS Duration of HG RFS represent the number of months from day 1 that a complete response within the bladder has been documented based on yearly report.
• CIS carcinoma in situ
• CR complete response
• HG high-grade
• HGD high-grade disease
• rAd-IFN ⁇ /Syn3, recombinant adenovirus interferon alpha protein/Syn3 ® a nonreplicating recombinant adenovirus gene transfer vector for patients with HG bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive-bladder cancer
• RFS relapse-free survival
• Ta papillary urothelial carcinoma confined to the mucosa
• T1 micro-invasive urothelial carcinoma invasive into lamina limbal but not muscularis propria.
• Gene expression analysis may be done using tumor biopsy samples.
• urine samples if properly preserved may contain exosomes which enable analysis of oncogene expression.
• Exosomes are small (30-100 nm) endocytic, cell-derived vesicles. They are secreted by most human cell types, including cancer cells, and they may be absorbed via endocytosis into recipient cells. Exosomes can contain functional bio-molecules such as dsDNA, and may be found in human blood and urine. Exosomal DNA (“exoDNA”) represents the entire genome and, where the exosome is produced from a tumor cell, reflects the mutational status of the tumor cell. ExoDNA in tumor-derived exosomes found in a urine sample taken from a bladder cancer patient thus provides a non-invasive circulating biomarker useful for the sensitive detection of cancer and a more accurate determination of potential responsiveness to interferon-based therapies.
• ExoDNA includes both single-stranded and double-stranded DNA. ExoDNA is found encapsulated in the interior of the exosome membrane and bound to the exterior of the exosome membrane. In internal exoDNA, dsDNA predominates. Typically, exoDNA encapsulated in the interior of the exosome membrane ranges from 0.1-2.5 kb, while exoDNA bound to the exosome membrane exterior is >2.5 kb. Much of the exoDNA associated with tumor exosomes is double-stranded DNA bound to the exterior of the exosome membrane. ExoDNA, which includes dsDNA, can provide an unusually accurate diagnostic tool because it provides a complete sample of the complete genome in readily-assayable form in the urine of a patient with bladder cancer.
• Micro vesicles are another type of extracellular vesicle, between 50 and 1,000 nanometers (nm) in diameter, found in many types of body fluids as well as the interstitial space between cells. Micro vesicles are made from fragments of plasma membrane. They are thus distinct from exosomes, which are smaller and generated intra-cellularly. In contrast to exosomes, which do not contain mitochondrial DNA, micro vesicles derived from astrocytes and glioblastoma include mitochondrial DNA. Micro vesicles appear equivalent to exosomes for the purposes of this invention.
• exosomes For a human patient diagnosed with bladder cancer, one may collect exosomes by collecting a urine sample. Sample storage techniques able to preserve DNA and RNA are known in the art. Similarly, isolation of exosomes from urine may be done using conventional separation techniques.
• FISH fluorescent in situ hybridization
• FISH is a molecular cytogenetic technique that uses fluorescent probes that bind to specific target parts of the chromosome, but when adequately stringent hybridization conditions are used, does so with a high degree of sequence complementarity.
• FISH was developed in the early 1980s. See e.g., Langer-Safer, P. R. et al., Immunological Method For Mapping Genes On Drosophila Polytene Chromosomes, 79 Proceedings of the National Academy of Sciences 4381 (1982).
• FISH can detect and localize the presence or absence of specific DNA sequences on chromosomes or in DNA fragments such as free DNA found in urine.
• the probe must be large enough to hybridize specifically with its target but not so large as to require non-stingent hybridization conditions, which conditions may lead to formation of false-positive hybridization to an inappropriate target sequence.
• the probe is tagged directly with fluorophores, with targets for antibodies or with biotin. Tagging can be done in various ways taught in the art, such as nick translation or Polymerase Chain Reaction using tagged nucleotides.
• FISH fluorescence microscopy
• RNA targets e.g., mRNA

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