Radiotherapy for BCG-unresponsive Non-muscle-invasive Carcinoma in Situ (CIS) Bladder Cancer: an Open-label, Single-arm, Multicentre, Phase 2 Study

Radiotherapy for BCG-unresponsive Non-muscle-invasive Carcinoma in Situ (CIS) Bladder Cancer

Standard treatment for patients with high-risk NMIBC (high-grade Ta, CIS, or any T1) consists of intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG, even administered optimally, does not provide absolute protection and BCG failure is generally considered recurrence or progression during therapy.

Patients who are BCG-unresponsive have a 20-40% risk for progression to muscle-invasive bladder cancer within 5 years, and a 50% risk of developing metastatic disease. For these patients, radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care. However, many patients are unable to undergo radical cystectomy because of poor performance status and co-morbidities or decline to undergo surgery.

Although, several phase II studies have shown promising results, none of the drugs are presently available in Europe. An alternative approach is to investigate a possible role for radiotherapy in good prognosis bladder cancer patients. As there is little existing data in NMIBC, the example of bladder preservation in MIBC will be used for guidance.

We aim to evaluate the use of radiotherapy in patients with high-grade non-muscle-invasive bladder cancer who have BCG failure in a single-arm design as per FDA guidelines for this setting. The primary objective is to demonstrate that complete response to treatment 6 months post radiotherapy is seen in more than 30% of patients with BCG-unresponsive, non-muscle invasive carcinoma in situ bladder cancer, unfit or unwilling to undergo radical cystectomy.

Patients with BCG unresponsive non-muscle-invasive bladder cancer according to the EAU guidelines will be treated 20 fractions of 2.75 Gy over 4 weeks with the use of radiosensitisers as per local guidelines. Cystoscopy and urine cytology assessments will be performed at 3 and 6 months from the start of radiotherapy. If either assessment is positive, bladder biopsies or TURBT are required. At the 6-month timepoint, biopsy or TURBT is mandatory. Disease assessments beyond 6 months will be at the treating urologist's discretion.

Inclusion Criteria:

• Histologically confirmed, BCG-unresponsive, high-risk non-muscle-invasive bladder cancer (according to EAU guidelines [2] (see table 1)) °of predominantly (>50%) urothelial histology who were ineligible for or declined to undergo radical cystectomy.

  • Patients with carcinoma in situ with or without high-grade Ta or T1 are allowed if patients with concomitant Ta and T1 tumors have undergone complete TURBT, defined as per standard of care as a visually complete resection. A second TURBT is recommended but not required for patients with T1 tumor.
  • The most recent cystoscopy or TURBT must have been done within 12 weeks before study enrolment.
  • Eastern Cooperative Oncology Group performance status of 0-2
  • Adequate organ function (at minimum WBC > 4.0 × 109/L; platelets > 100 × 109/L; GFR > 25mL/min)
  • 18 years or older
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 72 hrs prior to the first day of radiation.
  • Patients of childbearing / reproductive potential should use adequate birth control measures during the study treatment period and for at least 4 weeks after the last day of radiation. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Such methods include:
  • Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
  • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
  • Intrauterine device (IUD)
  • Intrauterine hormone-releasing system (IUS)
  • Bilateral tubal occlusion
  • Vasectomized partner
  • Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
  • Before patient 's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

• Evidence of muscle invasive or metastatic urothelial carcinoma
• Evidence of upper urinary tract carcinoma
• Poor bladder function (IPSS >16)
• Hydronephrosis due to tumour in the presence of T1 disease
• Patients on current systemic therapy for bladder cancer
• Patients who have received pelvic external beam radiotherapy within the previous 5 years
• Any known contraindications or allergies to the use of local standard of care radiosensitiser, if applicable