IZABRIGHT-BLADDER01: A Randomized, Open-label, Phase 2/3 trial of Izalontamab Brengitecan versus platinum-based chemotherapy for metastatic urothelial cancer in participants with disease progression on or after an immunotherapy-based treatment

This trial investigates izalontamab brengitecan in participants with metastatic urothelial cancer who experienced disease progression during or following immunotherapy-based treatment. The primary objective in Phase 2 is to determine the recommended dose of izalontamab brengitecan for use in Phase 3 of the trial. The primary objective in Phase 3 is to evaluate the efficacy endpoints of izalontamab brengitecan compared to platinum-based chemotherapy, where efficacy endpoints are measurements that assess how well the study treatment works. The secondary objectives include: Phase 2 evaluation of efficacy endpoints of two different doses of izalontamab brengitecan and assessment of how the drug is processed by the body (pharmacokinetics); Phase 3 evaluation of the efficacy of izalontamab brengitecan versus platinum-based chemotherapy. The comparator regimens include carboplatin, cisplatin, and gemcitabine, representing standard platinum-based chemotherapy options for this patient population.

This clinical trial enrolled a total of **254 participants** diagnosed with **metastatic urothelial cancer**. The study population included both **male and female adults** and older adults, reflecting the demographic distribution typical of this malignancy. Participants were selected based on histologically or cytologically confirmed disease that had progressed during or following **immunotherapy-based treatment**. Eligible individuals had received no more than two prior lines of **systemic cancer treatment** and demonstrated disease progression after **anti-PD-(L)1 therapy**, administered either as monotherapy or in combination with other agents, with at least one additional prior treatment line beyond the anti-PD-(L)1 regimen. Patients whose only anti-PD-(L)1 exposure occurred in the non-metastatic setting were excluded, though those who received such therapy in the perioperative context could qualify under specific conditions. A key requirement for participation was the ability to tolerate **platinum-based chemotherapy**, specifically **cisplatin** or **carboplatin**, as this formed part of the comparator treatment arm. The trial did not involve vulnerable populations.

This clinical trial is designed as a **randomized**, **open-label**, **Phase 2/3** study evaluating **izalontamab brengitecan** compared to **platinum-based chemotherapy** in participants with **metastatic urothelial cancer** who have experienced disease progression on or after **immunotherapy-based treatment**. The trial will investigate the efficacy, safety, tolerability, and pharmacokinetic properties of the investigational medicinal product. The study involves the administration of izalontamab brengitecan as the test product, while the comparator arms include **carboplatin**, **gemcitabine**, and **cisplatin**, all administered via **intravenous use**. **Pegfilgrastim**, administered via **subcutaneous** route, serves as an auxiliary medicinal product. The investigational product is formulated as a **powder for solution for infusion** containing the active substance izalontamab brengitecan, which is of biological/biotechnological origin.

The trial is divided into two phases with distinct objectives. Phase 2 aims to determine the recommended dose of izalontamab brengitecan for use in Phase 3 by reviewing all available data, including efficacy, safety, tolerability, and pharmacokinetic parameters. Phase 3 focuses on evaluating the efficacy of izalontamab brengitecan compared to platinum-based chemotherapy through primary endpoints including **progression-free survival**, defined as the time from the start of treatment until disease worsening or death, whichever occurs first, and **overall survival**, which measures how long participants live. Secondary endpoints in both phases include **objective response rate**, **time to response**, **duration of response**, progression-free survival, and overall survival. In Phase 3, an additional secondary endpoint assesses the time to decline in participants' quality of life.

Eligible participants must have metastatic urothelial cancer confirmed by tissue or cell sample analysis, with documented disease progression during or after immunotherapy-based treatment. Participants must not have received more than two prior lines of systemic cancer treatment. The disease must have progressed or recurred after treatment with anti-PD-(L)1 therapy, either alone or in combination with other treatments, with at least one additional treatment line beyond anti-PD-(L)1 therapy. Participants who received anti-PD-(L)1 therapy solely for non-metastatic bladder cancer are excluded. Those who received anti-PD-(L)1 therapy as perioperative treatment may be eligible if specific conditions are met. Participants must be suitable candidates for platinum-based chemotherapy with cisplatin or carboplatin.

The dosing regimens for the comparator products are as follows: gemcitabine with a maximum daily dose of 1000 mg/m² and a maximum total dose of 6000 mg/m² over a treatment period of 6 cycles; carboplatin with a maximum treatment period of 6 cycles; cisplatin with a maximum daily dose of 70 mg/m² and a maximum total dose of 420 mg/m² over 6 cycles; and pegfilgrastim with a maximum daily dose of 9999 mg over an extended treatment period. The investigational product izalontamab brengitecan has a maximum daily dose of 9999 mg and a maximum total dose of 9999 mg with an extended treatment period. The trial is estimated to commence recruitment in October 2025 and is expected to conclude in October 2029, representing an overall trial duration of approximately four years. Participant involvement will vary depending on treatment response, tolerability, and disease progression. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, participant withdrawal of consent, or investigator decision based on safety concerns.

The experimental medication **BL-B01D1** (sponsor product code **BMS986507**) contains the active substance **izalontamab brengitecan**, a biological product of biotechnological origin. The medication is supplied as a **powder for solution for infusion** and is administered via the **intravenous route**. The maximum daily dose and maximum total dose are specified as 9999 milligrams, with a maximum treatment period of 9999 days. The product will be removed from the carton, over-labeled, and repackaged prior to use in the trial.

**Gemcitabine** is administered as a comparator treatment in this clinical trial. The medication is supplied as a **powder for solution for infusion** and is administered via **intravenous use**. The dosage is expressed in milligrams per square meter, with a maximum daily dose of 1000 mg/m² and a maximum total dose of 6000 mg/m². The maximum treatment period is 6 cycles. The product will be removed from the carton, over-labeled, and repackaged before administration.

**Carboplatin** serves as a comparator treatment and is supplied as a **concentrate for solution for infusion** for **intravenous use**. The dosage is expressed in milligrams per milliliter, with maximum daily and total doses specified as 9999 mg/ml. The maximum treatment period is 6 cycles. The product will be removed from the carton, over-labeled, and repackaged prior to use.

**Cisplatin** is utilized as a comparator treatment in the study. The medication is supplied as a **concentrate for solution for infusion** and administered via **intravenous use**. The dosage is expressed in milligrams per square meter, with a maximum daily dose of 70 mg/m² and a maximum total dose of 420 mg/m². The maximum treatment period is 6 cycles. The product will be removed from the carton, over-labeled, and repackaged before administration.

**Pegfilgrastim** is included as an auxiliary medicinal product in the trial. The medication is supplied as a **solution for injection** and is administered via the **subcutaneous route**. The dosage is expressed in milligrams, with maximum daily and total doses specified as 9999 mg. The maximum treatment period is 9999 days. The product will be removed from the carton, over-labeled, and repackaged prior to administration.

Efficacy will be assessed differently in Phase 2 and Phase 3 of this clinical trial. In Phase 2, the evaluation will involve reviewing all available data, including efficacy, safety, tolerability, and pharmacokinetic data, to determine the recommended dose of izalontamab brengitecan for use in Phase 3. In Phase 3, efficacy will be evaluated by comparing progression-free survival, defined as the time from start of treatment until disease progression or death, whichever occurs first, and overall survival, defined as how long a patient lives, between izalontamab brengitecan and platinum-based chemotherapy.

Additional efficacy endpoints will be assessed in both Phase 2 and Phase 3, including objective response rate, which measures the proportion of participants who respond to treatment, time to response, duration of response, progression-free survival, and overall survival. In Phase 3 only, the time to deterioration in patient-reported quality of life will be measured and compared between treatment groups.