The Cxbladder Rule-out of Recurrent Urothelial Carcinoma

Bladder Cancer Clinical Trial

Official title:

A Clinical, Non-intervention Study of the Cxbladder Urine Test for the Detection of Recurrent Urinary Tract Urothelial Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03673202
• Other study ID #: Waiting
• Status: Recruiting
• Start date: November 26, 2018
• Est. completion date: November 2020

Study information

• Verified date: August 2019
• Source: London Health Sciences Centre
• Contact: Shiva M Nair, MD, PhD
• Phone: 5196858500
• Email: shiva.nair[@]lhsc.on.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This observational study is designed to collect urine and relevant clinical information from patients who have a known diagnosis of bladder cancer and currently on clinically driven surveillance. The study aims to compare the urine test to the flexible cystoscopy procedure (which the patient is already scheduled).

Description:

There are approximately 360,000 new cases of bladder cancer diagnosed globally each year. In addition, this disease is responsible for 145,000 deaths annually (Parkin et al 2005). Treatments for this cancer range from transurethral resection of the bladder tumor (TURBT) for low stage, non-invasive tumors, to the more drastic option of radical cystectomy with pelvic lymph node dissection for those tumors that are found to have invaded into the muscularis propria (Parekh et al 2006). Currently, the standard of care for diagnosing bladder cancer involves a combination of flexible cystoscopy and urine cytology, which is usually performed after the patient presents with episodes of gross hematuria. Following these evaluations, if evidence exists that warrants further investigation for bladder cancer a TURBT is performed and accurate staging and grading of the tumor can occur (O'Sullivan et al 2012). For those patients who have localized disease and have bladder preservation therapies, long term surveillance (in high grade disease this is life-long) is required to monitor for recurrence of tumor (Sylvester et al 2006). While cystoscopy has proven to be an accurate tool (sensitivity 80%) in the surveillance of bladder cancer, it is nonetheless a highly invasive procedure (Jocham et al 2008). In addition, urine cytology, which has served as the traditional adjunct to cystoscopy operates with a modest degree of sensitivity and therefore potential to deliver false negatives where malignant cells are not seen and false positives for bladder cancer in patients with an acute or chronically inflamed urothlelium (Grossman et al 2005). This leaves room for the development of a diagnostic test that is able to deliver results with the specificity of cystoscopy but without the potential for false negatives seen with urine cytology.

Recently, studies have shown that certain genetic markers exist that accompany the occurrence of bladder cancer and can accurately discriminate between bladder tumors and normal tissue. These genetic markers also show promise in being able to deliver additional information regarding the disease state of this cancer, such the stage and grade of the tumor (Dyrskjot et al 2003; Dyrskjot et al 2005; Thykjaer et al 2001). The informative nature of these mRNA expression profiles, along with the frequency with which tumor exfoliation into the urine occurs, has led to the development of a urine-based test that has the potential to diagnose and stratify bladder cancer. This urine test, known as Cxbladder Monitor, was developed by Pacific Edge Limited and is able to perform a combinatory analysis of the expression profiles of five genetic biomarkers (IGF, HOXA, MDK, CDC and IL8R gene expression) and two clinical variables (whether the previous tumor was primary or recurrent and the time since the previous tumor was resected). This test has the potential, with further testing, to produce a consolidated diagnostic score that is able to accurately risk stratify a given patient for recurrence of bladder cancer based on tumor characteristics. The five genetic markers include CDC2 (a gene involved in cell cycle activity and DNA synthesis) (O'Sullivan et al 2012), HOXA13 (transcription factor involved in morphogenesis and differentiation of the genitourinary tract) (Scott et al 2005), IGFBP5 (affects processes such as such as development, differentiation, and cellular survival) (Beattie et al 2006), MDK (a heparin binding growth factor expressed during embryogenesis) (Kadomatsu et al 2004), and CXCR2 which is expressed in neutrophils and is increased in non-malignant, inflammatory conditions. This marker is essential as it is helpful in reducing the risk of false positive results in patients with an inflamed urothelium (O'Sullivan et al 2012). The Cxbladder test is able to take into account the expression of all these relevant genetic markers and analyze their expression profiles and interactions via a 2 way linear discriminate algorithm to form a score that is able to predict the recurrence of bladder cancer. The success of these preliminary studies with Cxbladder show that it has a strong potential to be used as a alternate to urine cytology and challenge cytology's routine accompaniment to cystoscopy. More importantly, the use of Cxbladder in the surveillance patient has the potential to decrease the frequency with which cystoscopy would need to be performed, adjudicate equivocal cystoscopy and cytology atypia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: November 2020
• Est. primary completion date: August 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patient is undergoing investigative cystoscopies for the monitoring of recurrence of urinary tract UC at intervals prescribed by the clinical practitioner

2. Patients on an "all-comers" basis

3. Positive diagnosis for primary or recurrent bladder tumour within the past 5 years

4. Able provide a voided urine sample of the required minimum volume

5. Able to give written consent

6. Able and willing to comply with study requirements

7. Aged 18 years or older

Exclusion Criteria:

1. Prior genitourinary manipulation (flexible or rigid cystoscopy / catheterisation, urethral dilation) in the 14 days before urine collection,

2. Patients who had exposure to intravesical BCG, had completed induction BCG but without a subsequent clear cystoscopy

3. Recent history of glomerulonephritis, nephrosis or other renal inflammatory disorders,

4. Recent history of pyelonephritis

5. Total cystectomy of the bladder, neo bladders and illeal conduits

6. Previous muscle invasive bladder tumour (pT2 or greater)

Related Conditions & MeSH terms

• Bladder Cancer
• Carcinoma, Transitional Cell
• Urinary Bladder Neoplasms

Intervention

Diagnostic Test:
• Cx bladder Monitor test
Cxbladder Monitor is a non-invasive UC detection test measuring five messenger RNA (mRNA) biomarkers present at elevated levels in patients presenting with urothelial carcinoma and also two clinical variables (whether the previous tumor was primary or recurrent and the time since the previous tumor was resected).

Locations

Country	Name	City	State
Canada	Victoria Hospital	London	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
London Health Sciences Centre	Pacific Edge Limited

Country where clinical trial is conducted

Canada, 

References & Publications (12)

Beattie J, Allan GJ, Lochrie JD, Flint DJ. Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. Biochem J. 2006 Apr 1;395(1):1-19. Review. — View Citation

Dyrskjøt L, Thykjaer T, Kruhøffer M, Jensen JL, Marcussen N, Hamilton-Dutoit S, Wolf H, Orntoft TF. Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet. 2003 Jan;33(1):90-6. Epub 2002 Dec 9. — View Citation

Dyrskjøt L, Zieger K, Kruhøffer M, Thykjaer T, Jensen JL, Primdahl H, Aziz N, Marcussen N, Møller K, Orntoft TF. A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res. 2005 Jun 1;11(11):4029-36. — View Citation

Grossman HB, Messing E, Soloway M, Tomera K, Katz G, Berger Y, Shen Y. Detection of bladder cancer using a point-of-care proteomic assay. JAMA. 2005 Feb 16;293(7):810-6. — View Citation

Jocham D, Stepp H, Waidelich R. Photodynamic diagnosis in urology: state-of-the-art. Eur Urol. 2008 Jun;53(6):1138-48. Epub 2007 Dec 10. Review. — View Citation

Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. Cancer Lett. 2004 Feb 20;204(2):127-43. Review. — View Citation

O'Sullivan P, Sharples K, Dalphin M, Davidson P, Gilling P, Cambridge L, Harvey J, Toro T, Giles N, Luxmanan C, Alves CF, Yoon HS, Hinder V, Masters J, Kennedy-Smith A, Beaven T, Guilford PJ. A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. J Urol. 2012 Sep;188(3):741-7. doi: 10.1016/j.juro.2012.05.003. Epub 2012 Jul 19. — View Citation

Parekh DJ, Bochner BH, Dalbagni G. Superficial and muscle-invasive bladder cancer: principles of management for outcomes assessments. J Clin Oncol. 2006 Dec 10;24(35):5519-27. Review. — View Citation

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108. — View Citation

Scott V, Morgan EA, Stadler HS. Genitourinary functions of Hoxa13 and Hoxd13. J Biochem. 2005 Jun;137(6):671-6. Review. — View Citation

Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW, Kurth K. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006 Mar;49(3):466-5; discussion 475-7. Epub 2006 Jan 17. — View Citation

Thykjaer T, Workman C, Kruhøffer M, Demtröder K, Wolf H, Andersen LD, Frederiksen CM, Knudsen S, Orntoft TF. Identification of gene expression patterns in superficial and invasive human bladder cancer. Cancer Res. 2001 Mar 15;61(6):2492-9. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of participants with bladder cancer who are correctly identified as having cancer (true positives) and no cancer (true negatives) by the Cxbladder test.	To validate the Performance Characteristics (sensitivity, area under the ROC curve, positive and negative predictive values and test negative rate) of the Cxbladder for the detection of recurrent UC in the absence of inflammation in patients with a recent history of urinary tract UC who have been treated according to standard practice and are undergoing routine investigative cystoscopy. The gold standard for determination of clinical truth is cystoscopy confirmed by pathology, plus any follow up investigations relating to the current visit.	24 months
Secondary	Detection rates of Cx bladder test	To define and the validate the Performance Characteristics of the Cxbladder for the detection of recurrent UC in local population patients with a recent history of urinary tract UC who have been treated according to standard practice and are undergoing routine investigative cystoscopy	24 months
Secondary	Comparison of Cxbladder theoretical capacity to reduce use of flexible cystoscopy for the monitoring for recurrence of urothelial carcinoma	To estimate the theoretical clinical outcome of patients under the Standard Of Care tested with Cxbladder before investigative cystoscopy to determine the true proportion requiring cystoscopy and follow up and thereby determining the potential of Cxbladder for reducing the cystoscopy burden on patients undergoing monitoring for recurrence	24 months
Secondary	Comparison of the Cxbladder test and cytology test performance on the same sample	Performance characteristics (sensitivity, specificity, rule-out rate, PPV and NPV) of the Cxbladder and urine cytology on the same voided urine sample.	12 months
Secondary	Performance of Cxbladder test in atypical findings of cytology and cystoscopy	To compare and contrast atypical cytology and / or equivocal cystoscopy with the performance characteristics of Cxbladder signatures	24 months
Secondary	Examine urinary microbiome profile in patients with urothelial cancer	Compare differences in microbiome profiles in patients with urothelial cancer and those without	24 months