A Phase III Randomised Control Clinical Trial of Radiotherapy With Radiosensitisation Versus Intravesical Bacillus Calmette-Guerin Therapy for High-risk Non-muscle Invasive Bladder Cancer. (TRAIN)

The Christie NHS Foundation Trust

Status and phase: Not yet enrolling; Phase 3

Conditions: High-Risk Non-Muscle Invasive Bladder Cancer

Treatments: Other: BCG; Radiation: radiotherapy

Study type: Interventional

Funder types: Other

Identifiers

NCT07268339

CFTsp223

Details and patient eligibility

About

In the UK 20,000 people develop urothelial bladder cancer each year with 75-80% having Non-Muscle Invasive Bladder Cancer (NMIBC). The current standard of care for patients with High Risk-NMIBC (HR-NMIBC) is either surgery to remove the tumour (transurethral resection of bladder tumour; TURBT) followed by BCG (Bacillus Calmette Guérin, an immunotherapy drug) given directly into the bladder, or surgery to remove the bladder (cystectomy). BCG is given weekly for six weeks followed by maintenance treatment up to 3 years. However, in up to 50% of patients their cancer returns (recurrence) or gets worse (progression) after BCG and 25% stop treatment due to side effects. Globally BCG supply has been restricted in recent years has increased HR-NMIBC recurrence rates and costs. Improved treatments are required, to prevent recurrence, progression and cystectomy, and mitigate the effects of unpredictable supply.

Trimodality treatment (TMT) is maximal TURBT + radiotherapy + a radiosensitiser (gemcitabine, mitomycin C/fluorouracil or carbogen/nicotinamide) and is an equivalent alternative treatment to cystectomy for muscle-invasive bladder cancer (MIBC). TMT is not routinely used for HR-NMIBC. A study found that 54% of HR-NMIBC patients who received TMT did not have recurrence within 5 years. Modern radiotherapy is expected to further improve outcomes and minimise side-effects.

Patients will be randomised 1:1 to BCG or radiotherapy with radiosensitisation. Patients randomised to the experimental arm will receive 55Gy in 20 fractions. Investigators can then choose from three different options for the radiosensitiser. TRAIN will test if radiotherapy with radiosensitisation improves outcomes for people with HR-NMIBC compared to BCG.

TRAIN will recruit 328 patients with HR-NMIBC following maximal TURBT. All patients will be followed up for a minimum of two years to record their response to treatment.

Enrollment: 328 estimated patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Diagnosed with histologically confirmed grade 3 T1 N0 M0 transitional cell carcinoma, OR carcinoma in situ of the bladder (and N0 M0), OR both, with detrusor muscle present in the biopsy specimen if T1 disease (or a repeat resection that does contain muscle that is clear)
• Suitable for BCG treatment
• Suitable for radiotherapy and radiosensitisation according to the schedule of administration outlined in the Radiotherapy Planning Guidance document.
• Life expectancy over 12 months
• ECOG performance status 0 - 2
• Age >=16 years
• Provided written informed consent

Exclusion criteria

• MDT selected patients with HR-NMIBC who are deemed best suited for primary cystectomy (patients that have had this treatment recommendation but then decline cystectomy remain eligible for TRAIN)
• Previous radiotherapy to the pelvis
• Previous intravesical therapy
• Poor bladder function (IPSS >16)
• A recent or current other cancer. Current non-melanoma skin cancer, cervical carcinoma in situ or localized prostate cancer not requiring current treatment are permissible, as is a history of a separate other malignancy having completed all active treatment ≥2 years previously and without evidence of relapse
• Pre-existing medical conditions that preclude treatment options in either trial arm
• Patient currently recruited to another interventional trial or participation within an interventional clinical trial within 3 months of the point of registration within TRAIN.
• Pregnant or breast-feeding
• Not able to use appropriate adequate effective contraception during and for 3 months after the study

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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328 participants in 2 patient groups

Control Arm: BCG

Active Comparator group

Description:

This arm is standard of care for this patient group. A standard protocol of 6 weekly intravesical installations, followed by 3 weekly instillations at approximately 3, 6, 12, 18, 24, 30 months and 36 months (depending on toxicity). Stock is taken and given per local hospital guildlines.

Treatment:

Other: BCG

Experimental Arm: Radiotherapy with Radiosentiser drugs.

Experimental group

Description:

Patients randomised to the radiotherapy arm will receive a hypofractionated schedule of external beam radiotherapy with a regimen of 55Gy in 20 fractions given once daily Monday to Friday over 4 weeks. Radiotherapy will be delivered with a conventional or 3D conformal technique with an empty bladder. It will be administered concurrently with a radiosensitiser (detailed below) selected by the treating physician according to local institutional practice. Radiosensitiser will be selected as one option from the following: * Gemcitabine 75-100mg/m2 administered once a week during a four-week radiotherapy course. Cycle 1 will be given on the first radiotherapy day, to a planned total of 4 cycles. 2-4 hours prior to radiotherapy * 5-FU and Mitomycin C - Fluorouracil 500mg/m2 Days 1-5 and 16-20 via continuous infusion. Mitomycin C 12mg/m2 Day 1 via intravenous infusion * Carbogen and nicotinamide (CON) - 2% CO2 and 98% O2 Carbogen will be delivered through a closed breathing system with

Treatment:

Radiation: radiotherapy