Phase I/II Study of Intravesical Eciskafusp Alfa and Bacillus Calmette-Guérin in BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

The primary objective of this study is to evaluate the **safety** and tolerability of eciskafusp alfa in combination with Bacillus Calmette-Guérin (BCG) in participants with BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC). Additionally, the study aims to determine the maximum-tolerated dose (MTD) and/or the recommended dose for extension (RDE) of eciskafusp alfa in combination with BCG. In Phase II, the primary focus is to assess the anti-tumor activity of the study treatment by evaluating the absence of high-risk NMIBC or progressive disease, as determined by cystoscopy, radiologic imaging, and retrospective central pathology review of cytology and biopsy. These objectives are clinically relevant as they aim to establish a safe and effective treatment regimen for patients with high-risk NMIBC who do not respond to standard BCG therapy.

Secondary objectives include:

• Evaluating the anti-tumor activity of the study treatment by assessing the absence of high-risk NMIBC or progressive disease through cystoscopy, radiologic imaging, and pathology review in both Phase I and Phase II (Cohorts A and B).
• Assessing the safety and tolerability of the study treatment in Phase II (Cohorts A and B).
• Evaluating the immune response against eciskafusp alfa intravesically during and after study treatment in both Phase I and Phase II (Cohorts A and B).
• Determining the association of baseline characteristics in the tumor microenvironment (TME) and urine with clinical outcomes in Phase II.
• Determining the pharmacodynamic effects of eciskafusp alfa in urine in Phase II.

The clinical trial involves a total of **6 participants** diagnosed with **BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific disease characteristics, including pathologically confirmed high-risk non-muscle invasive transitional cell carcinoma, with carcinoma in situ (CIS) present. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, depending on the phase of the study. Participants must have BCG-unresponsive disease, defined by persistent or recurrent CIS within 12 months of adequate BCG therapy. The trial population is considered vulnerable, and the selection process ensures that participants are either ineligible for radical cystectomy or have elected not to undergo the procedure. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **Phase I/II, open-label, dose escalation and extension study** to evaluate the safety, tolerability, and anti-tumor activity of eciskafusp alfa in combination with **Bacillus Calmette-Guérin (BCG)** in participants with BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC). The trial will be conducted in two phases: Phase I aims to determine the maximum-tolerated dose (MTD) and/or the recommended dose for extension (RDE) of eciskafusp alfa in combination with BCG, while Phase II will assess the anti-tumor activity by evaluating the absence of high-risk NMIBC or progressive disease. The study is expected to commence recruitment on March 1, 2025, and conclude by October 31, 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as the presence of pathologically confirmed high-risk non-muscle invasive transitional cell carcinoma and BCG-unresponsive disease. The trial will include regular follow-up visits to monitor the incidence, nature, and severity of adverse events, as well as the anti-tumor response through cystoscopy, radiologic imaging, and pathology review. The end-of-study visit will evaluate the complete response rate at 12 months and other secondary endpoints such as progression-free survival and time to cystectomy.

The expected length of participant involvement will vary depending on the phase and cohort, with specific time points for evaluating the duration of response and other outcomes. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities or adverse events that compromise participant safety. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity and reliability of the data collected throughout the study duration.

The clinical trial involves the administration of **BCG-MEDAC**, a pharmaceutical product formulated as a **poudre et solvant pour suspension intravésicale**. This product contains the active substance **BCG (Bacillus Calmette-Guérin), live attenuated, strain RIVM (strain 1173-P2 derived)**. The product is intended for **intravesical use** and is supplied by MEDAC Gesellschaft für klinische Spezialpräparate mbH (Wedel). The BCG-MEDAC is classified under the ATC code **L03AX03**, indicating its use as a BCG vaccine. The administration schedule and dosage are determined based on the study protocol, with compliance monitored through standard clinical trial procedures.

Another investigational product used in the trial is **PD1IL2v iMAb**, which is provided as a **solution for injection/infusion**. The active substance in this product is **RO7284755**, a protein-based compound. This product is also administered via the **intravesical route**. The sponsor of this investigational product is F. Hoffmann-La Roche Ltd. The dosing regimen and frequency of administration are specified in the trial protocol, with adherence to the treatment plan being closely monitored to ensure participant compliance.

Both investigational products are utilized in combination to evaluate their safety, tolerability, and anti-tumor activity in participants with BCG-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC). The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study is designed to determine the maximum-tolerated dose (MTD) and/or the recommended dose for extension (RDE) of the investigational products when used in combination.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Phase I include the incidence, nature, and severity of adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), the nature and frequency of dose-limiting toxicities (DLTs), and the recommended dose for extension (RDE) based on safety evaluation. For Phase II, the primary endpoint is the complete response (CR) rate at 12 months in participants with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to Bacillus Calmette-Guérin (BCG) therapy.

Secondary endpoints will be evaluated across both Phase I and Phase II, including the CR rate at various time points (6, 12, 18, and 24 months), duration of response (DoR), and progression-free survival (PFS) to muscle invasive or metastatic disease or death. Additional assessments will include the time to worsening of grade or stage, time to cystectomy, and the incidence and severity of AEs. In Phase II, the study will also measure the incidence and titer of eciskafusp alfa anti-drug antibodies (ADAs), pre-treatment and on-treatment PD-L1 expression in the tumor microenvironment (TME), pre-treatment CD8+ T cell prevalence, and changes in urine tumor DNA from baseline.