S1602, A Phase III Randomized Trial to Evaluate the Influence of BCG Strain Differences and T Cell Priming With Intradermal BCG Before Intravesical Therapy for BCG-Naive High-Grade Non-muscle Invasive Bladder Cancer

Southwest Oncology Group (SWOG)
Study Design: 
S1602 also known as the “PRIME” study is a three-arm, phase III trial that will compare the effect of BCG strains (Tokyo vs TICE) and the effect of intradermal priming before intravesical instillation in patients with BCG-naïve high-grade non-muscle invasive bladder cancer. Eligible patients will be randomized to either standard intravesical TICE strain BCG or Tokyo-172 strain BCG or priming (intradermal Tokyo-172) followed by intravesical Tokyo-172 BCG. The accrual goal is 969 patients (323 patients per arm).
Pre-existing immunity as suggested by a positive purified protein derivative (PPD) test is associated with a higher recurrence-free survival rate after BCG therapy in both patients and pre-clinical murine models. Furthermore, initial reports of BCG therapy in bladder cancer by Morales et al described subcutaneous BCG vaccination of patients concurrent with intravesical BCG. However, patients today are no longer treated with intradermal BCG vaccination at the time of intravesical instillation and are often treated without regard to their PPD status. Therefore, this trial evaluates whether intradermal priming 3 weeks before intravesical BCG instillation improves outcomes at one year compared to intravesical BCG instillation without priming. In addition, given the recent shortage of TICE and Connaught BCG strains and the announcement that Sanofi will no longer manufacture the BCG TICE strain, this trial evaluates treatment response with the Tokyo BCG strain as well.
The primary endpoint is time to high-grade recurrence. The secondary endpoint is disease-free rates at 6 months.
The primary objectives are: (1) to demonstrate non-inferiority of Tokyo-172 BCG strain compared to TICE and (2) to test the hypothesis that intravesical Tokyo-172 BCG with priming is superior to intravesical Tokyo-172 BCG without priming. All groups will undergo BCG induction followed by maintenance therapy as per the SWOG protocol. This trial is aimed at BCG-naïve patients and therefore it will be extremely important that each academic center reach out to local community urologists and encourage trial participation and/or patient referrals in order to successfully accrue the nearly 1000 patients required for this trial as these are the urologists who routinely see BCG-naïve disease.