Neoadjuvant Short-term Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in NMIBC (NICSA)

• ClinicalTrials.gov Identifier: NCT03348969
• Recruitment Status: Active, not recruiting
• First Posted: November 21, 2017
• Last Update Posted: January 13, 2021
• Sponsor: Jørgen Bjerggaard Jensen
• Information provided by (Responsible Party): Jørgen Bjerggaard Jensen, Aarhus University Hospital

Tracking Information

• First Submitted Date: November 13, 2017
• First Posted Date: November 21, 2017
• Last Update Posted Date: January 13, 2021
• Actual Study Start Date: November 1, 2017
• Actual Primary Completion Date: June 11, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 16, 2017)

2-year recurrence rate [ Time Frame: within 2 years ]

The primary outcome is the number of patients in need for a TURB or tumour fulguration in the first 2 years following randomization. TURBs included as primary endpoint are the initial TURB in the control group, the prospective TURB in the intervention group for patients without complete chemoresection as well as TURB due to recurrence in both study groups. In case a TURB is recommended, but a subject refuses to undergo surgery, the recommended TURB is also registered.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 13, 2019)

• Tumour response rate [ Time Frame: 6 months after complete enrollment ]
  Number of patients with complete, partial and incomplete tumour response on neoadjuvant, short-term intensive chemoresection with Mitomycin C.
• 5-year recurrence rate [ Time Frame: within 5 years ]
  The number of patients in need of a TURB or tumour fulguration in the outpatient clinic in the first 5 years following randomization. TURBs included are the initial TURB in the control group, the prospective TURB in the intervention group for patients without complete chemoresection as well as TURB due to recurrence in both study groups. In case a TURB is recommended, but a subject refuses to undergo surgery, the recommended TURB is also registered.
• Adverse events [ Time Frame: 6 months after complete enrollment ]
  Proportion of patients with adverse events related to neoadjuvant, short-term intensive chemoresection
• Biomarkers [ Time Frame: within 2 years ]
  Composition of 650 cancer-associated genes expressed on the last resected tumour

Original Secondary Outcome Measures (submitted: November 16, 2017)

5-year recurrence rate [ Time Frame: within 5 years ]

Outcome number two is the number of patients in need of a TURB or tumour fulguration in the outpatient clinic in the first 5 years following randomization. TURBs included as primary endpoint are the initial TURB in the control group, the prospective TURB in the intervention group for patients without complete chemoresection as well as TURB due to recurrence in both study groups. In case a TURB is recommended, but a subject refuses to undergo surgery, the recommended TURB is also registered.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Neoadjuvant Short-term Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in NMIBC
• Official Title: Neoadjuvant Short-term Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in NMIBC
• Brief Summary: A randomized controlled trial aiming to investigate neoadjuvant, short-term intensive chemoresection with Mitomycin C compared to standard treatment with TURB and adjuvant intravesical instillation therapy in patients with recurrent non-muscle invasive bladder cancer (NMIBC).

Detailed Description

Background:

Bladder cancer is the 11th most common cancer in the world and one of the most costly cancers on a per patient basis, due to the cost of operative procedures, follow-up cystoscopies and instillation therapy. Furthermore there is a risk of progression to invasive and hence deadly cancer why efficient and immediate treatment is crucial. Treatment today consists of surgical removal of tumours (TURB) and adjuvant intravesical treatment. There is a chance; neoadjuvant intravesical treatment with chemotherapy can supersede surgical removal in chemo-sensitive tumours while however some tumours will not respond to intravesical chemotherapy. Currently it is not possible to predict which tumours are chemo-sensitive and which are not.

Objectives:

To assess the efficacy of neoadjuvant, short-term intensive chemoresection with Mitomycin C compared to standard treatment with TURB and adjuvant intravesical instillation therapy in patients with recurrent non-muscle invasive bladder cancer (NMIBC).

To investigate the ability to predict chemo-response in patients with recurrent non-muscle invasive bladder cancer (NMIBC).

Methods:

A randomised clinical controlled trial will include 120 patients with recurrent NMIBC.

The control group of 60 patients will receive standard care with TURB and adjuvant intravesical treatment. The intervention group of 60 patients will be submitted to neoadjuvant short-term intensive chemoresection with three instillations with Mitomycin C per week for two weeks. Remnant tumour tissue will be evaluated by flexible cystoscopy after four weeks.

To investigate the ability to predict chemo-response in patients with recurrent NMIBC, a connection between biomarkers of the initial tumour tissue and tumour response will be assessed.

Samples of the latest resected tumour prior to inclusion will be collected from all participants treated with neoadjuvant chemoresection and assessed against the tumour response seen in the trial.

Perspectives:

Validation of biomarkers to predict chemo-response will be an important step to integrate biomarkers in daily clinical practice and to individualize the treatment of NMIBC.

In some cases surgery could be avoided while ineffective chemotherapy could be avoided in others.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized Clinical Trial

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Bladder Cancer

Intervention

Drug: Mitomycin c

Neoadjuvant Mitomycin C

Other Name: Mitomycin "Medac"

Study Arms

• Experimental: Intervention
  Neoadjuvant Mitomycin C
  Intervention: Drug: Mitomycin c
• Active Comparator: Control
  Adjuvant Mitomycin C
  Intervention: Drug: Mitomycin c

Publications *

• Herr H. Re: Marko Babjuk, Andreas Böhle, Maximilian Burger, et al. EAU Guidelines on Non-muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017;71:447-61. Eur Urol. 2017 Jun;71(6):e171-e172. doi: 10.1016/j.eururo.2016.11.030. Epub 2016 Dec 12.
• Maffezzini M. Re: Richard J. Sylvester, Adrian P.M. van der Meijden, Willem Oosterlinck, J. Alfred Witjes, Christian Bouffioux, Louis Denis and Donald W.W. Newling. 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;49:466-77. Eur Urol. 2006 Sep;50(3):623-4; author reply 624-5. Epub 2006 May 4.
• Kaasinen E, Wijkström H, Rintala E, Mestad O, Jahnson S, Malmström PU. Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder. Scand J Urol. 2016 Oct;50(5):360-8. doi: 10.1080/21681805.2016.1210672. Epub 2016 Aug 15.
• Lamm DL. Preventing progression and improving survival with BCG maintenance. Eur Urol. 2000;37 Suppl 1:9-15. Review.
• Shelley MD, Wilt TJ, Court J, Coles B, Kynaston H, Mason MD. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 2004 Mar;93(4):485-90. Review.
• Shida K, Shimasaki J, Takahashi H, Kurihara H, Sato J. [Therapy and prognosis of bladder tumors--result of injection of mitomycin C into the bladder]. Gan No Rinsho. 1970 Jul;16(7):737-44. Japanese.
• Colombo R, Rocchini L, Suardi N, Benigni F, Colciago G, Bettiga A, Pellucchi F, Maccagnano C, Briganti A, Salonia A, Rigatti P, Montorsi F. Neoadjuvant short-term intensive intravesical mitomycin C regimen compared with weekly schedule for low-grade recurrent non-muscle-invasive bladder cancer: preliminary results of a randomised phase 2 study. Eur Urol. 2012 Nov;62(5):797-802. doi: 10.1016/j.eururo.2012.05.032. Epub 2012 May 18. Erratum in: Eur Urol. 2019 Mar;75(3):e81.
• Sousa A, Inman BA, Piñeiro I, Monserrat V, Pérez A, Aparici V, Gómez I, Neira P, Uribarri C. A clinical trial of neoadjuvant hyperthermic intravesical chemotherapy (HIVEC) for treating intermediate and high-risk non-muscle invasive bladder cancer. Int J Hyperthermia. 2014 May;30(3):166-70. doi: 10.3109/02656736.2014.900194. Epub 2014 Apr 3.
• Miyata Y, Sakai H. Predictive Markers for the Recurrence of Nonmuscle Invasive Bladder Cancer Treated with Intravesical Therapy. Dis Markers. 2015;2015:857416. doi: 10.1155/2015/857416. Epub 2015 Nov 23. Review.
• Seo HK, Cho KS, Chung J, Joung JY, Park WS, Chung MK, Lee KH. Prognostic value of p53 and Ki-67 expression in intermediate-risk patients with nonmuscle-invasive bladder cancer receiving adjuvant intravesical mitomycin C therapy. Urology. 2010 Aug;76(2):512.e1-7. doi: 10.1016/j.urology.2010.04.040. Epub 2010 Jun 26.
• Chen JX, Deng N, Chen X, Chen LW, Qiu SP, Li XF, Li JP. A novel molecular grading model: combination of Ki67 and VEGF in predicting tumor recurrence and progression in non-invasive urothelial bladder cancer. Asian Pac J Cancer Prev. 2012;13(5):2229-34.
• Karam JA, Lotan Y, Ashfaq R, Sagalowsky AI, Shariat SF. Survivin expression in patients with non-muscle-invasive urothelial cell carcinoma of the bladder. Urology. 2007 Sep;70(3):482-6.
• Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014 Jan;21(1):15-25. doi: 10.1038/cdd.2013.67. Epub 2013 Jun 21. Review.
• Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2017 Jan 26;168(3):542. doi: 10.1016/j.cell.2017.01.010.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 16, 2017): 120
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 31, 2021
• Actual Primary Completion Date: June 11, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Known history of urothelial non-invasive Ta-tumour low-grade or high-grade.
• ≥18 years old
• Mentally healthy individual
• The ability to understand Danish orally and in writing

Exclusion Criteria:

• Known history of invasive tumour of the bladder (T1+)
• Known history of CIS of the bladder
• Previous BCG-treatment within the last 24 months
• Previous Mitomycin C-treatment (except single-shot postoperative instillation)
• Known allergy or intolerance to Mitomycin C
• Solid tumour with suspicions of invasion
• Single tumour of more than 2 cm in diameter
• Suspicion of CIS (positive cytology with high-grade neoplastic cells combined with suspicious cystoscopy for flat lesions).
• Small bladder volume (less than 100 ml) or incontinence
• Acute cystitis
• Pregnancy or breast-feeding
• Not willing to use secure contraception with regard to men with partners and premenopausal women

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT03348969
• Other Study ID Numbers: DaBlaCa13
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Jørgen Bjerggaard Jensen, Aarhus University Hospital
• Study Sponsor: Jørgen Bjerggaard Jensen
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jørgen Bjerggaard Jensen, MD; Aarhus University Hospital

• PRS Account: Aarhus University Hospital
• Verification Date: January 2021