IZABRIGHT-Breast01: A Randomized, Open-label, Inferentially Seamless Phase 2/3 Study of Izalontamab Brengitecan (BMS-986507) versus Treatment of Physician’s Choice in Patients with Previously Untreated, Locally Advanced, Recurrent Inoperable, or Metastatic Triple-negative Breast Cancer (TNBC) or ER-low, HER2-negative BC who are Ineligible for Anti-PD1/PD-L1 Treatment

The primary objective of this study is to determine the optimal dose of izalontamab brengitecan and to evaluate its efficacy compared to standard chemotherapy regimens selected by the treating physician (including paclitaxel, nab-paclitaxel, capecitabine, or carboplatin plus gemcitabine) in patients with triple-negative breast cancer or ER-low, HER2-negative breast cancer that is locally advanced, recurrent inoperable, or metastatic. This objective is clinically relevant as it addresses the need for effective therapeutic options in patients with advanced breast cancer subtypes who are ineligible for anti-PD-1/PD-L1 therapy and have not received prior systemic treatment for advanced disease.

The secondary objectives of this study include:

• To evaluate overall survival in patients treated with izalontamab brengitecan compared to those receiving standard chemotherapy regimens.

• To compare the efficacy, safety profile, and tolerability of izalontamab brengitecan with standard chemotherapy treatments.

• To assess whether quality of life is superior in patients receiving izalontamab brengitecan compared to those receiving standard chemotherapy regimens.

• To compare the safety and efficacy of two different dose levels of izalontamab brengitecan relative to standard chemotherapy treatments.

This clinical trial enrolled a total of **341 participants** diagnosed with **triple-negative breast cancer** or **ER-low, HER2-negative breast cancer**. The study population included both **male and female** participants, comprising **adults** and **older adults**. Participants were selected based on having **advanced breast cancer** that was either **locally advanced**, **recurrent inoperable**, or **metastatic**, with disease that could not be surgically removed or had spread to other parts of the body. Eligible individuals had not received prior systemic therapy in the advanced or metastatic setting and were required to have **measurable disease** as defined by RECIST v1.1 criteria, including cases with bone-only disease provided a soft tissue component was present. Participants were required to have an **ECOG performance status** of 0 or 1, indicating good functional capacity. Key selection criteria included completion of all prior local cancer treatments at least 2 weeks before enrollment, recovery from previous treatment toxicities to Grade 1 or less, and eligibility for at least one of the specified chemotherapy options. Participants with triple-negative breast cancer were required to be ineligible for first-line chemotherapy combination treatment with **anti-PD-1** or **anti-PD-L1** agents, while those with ER-low, HER2-negative breast cancer were deemed ineligible for endocrine therapy-based treatments.

This is a randomized, open-label, inferentially seamless phase 2/3 clinical trial evaluating izalontamab brengitecan (BMS-986507) compared to treatment of physician's choice in participants with previously untreated, locally advanced, recurrent inoperable, or metastatic triple-negative breast cancer or ER-low, HER2-negative breast cancer who are ineligible for anti-PD-1/PD-L1 treatment. The investigational product is BL-B01D1, a powder for solution for infusion containing izalontamab brengitecan, administered via intravenous use. The comparator treatments selected by the physician include paclitaxel, paclitaxel albumin-bound, capecitabine, or a combination of carboplatin plus gemcitabine. Pegfilgrastim is included as an auxiliary medicinal product administered via subcutaneous use. The maximum treatment period is 260 days for all comparator agents, while the investigational product may be administered for up to 9999 days. The trial is designed to determine the appropriate dose of izalontamab brengitecan and to assess whether it demonstrates superior efficacy compared to standard chemotherapy options.

The primary objective of the study is to evaluate progression-free survival as assessed by blinded independent central review using radiographic imaging techniques. The secondary objective is to assess overall survival in participants receiving izalontamab brengitecan compared to those receiving physician's choice chemotherapy. The trial will enroll participants with advanced triple-negative breast cancer or ER-low, HER2-negative breast cancer that cannot be surgically removed or has metastasized, who have not received prior systemic therapy in the locally advanced, recurrent inoperable, or metastatic setting. Participants with triple-negative breast cancer must be considered ineligible for first-line chemotherapy combination treatment with an anti-PD-1 or anti-PD-L1 agent. Participants with ER-low, HER2-negative breast cancer must be ineligible for endocrine therapy-based treatments in the opinion of the investigator.

Key inclusion criteria require participants to have measurable disease by CT or MRI according to RECIST v1.1, including bone-only disease with a soft tissue component. Participants must undergo brain MRI within 28 days prior to randomization, or CT scan if MRI is contraindicated. Eligibility for at least one of the chemotherapy options listed as treatment of physician's choice must be confirmed by investigator assessment. Participants must have an ECOG performance status of 0 or 1 and must have recovered from all toxicities from previous systemic therapies to Grade 1 or less by NCI CTCAE v5.0, except for alopecia or peripheral neuropathy which may be Grade 2 or less at the time of randomization. All prior local cancer treatments, including radiotherapy and major surgery, must have been completed at least 2 weeks prior to randomization. No previous systemic therapy is permitted in the locally advanced, recurrent inoperable, or metastatic setting.

The estimated recruitment start date is October 2025, with an estimated end date of February 2031, indicating an overall trial duration of approximately 5 years and 4 months. The trial follows a randomized, open-label design, meaning participants and investigators will be aware of the assigned treatment, while efficacy assessments by independent central review will remain blinded. Participants will undergo screening procedures to confirm eligibility, followed by randomization to either the investigational arm or one of the physician's choice chemotherapy regimens. Study visits will include baseline assessments, regular treatment visits for drug administration and safety monitoring, and periodic imaging assessments to evaluate disease progression. Participants will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons for discontinuation. Long-term follow-up for survival will continue after treatment discontinuation until the end of the study.

The experimental medication under investigation is **BL-B01D1** (sponsor product code: BMS986507), containing the active substance **izalontamab brengitecan**. This investigational product is of biological/biotechnological origin and is supplied as a **powder for solution for infusion**. The medication is administered via **intravenous use**. The maximum daily dose amount is 9999 mg/kg and the maximum total dose amount is 9999 mg/kg, with a maximum treatment period of 9999 days. BL-B01D1 serves as the test product in this clinical trial.

**Paclitaxel albumin-bound** is utilized as one of the comparator treatments in this study. This medicinal product is provided as a **powder for dispersion for infusion** and contains paclitaxel albumin-bound as the active substance of specified substance group 1 origin. Administration is performed via **intravenous use**. The maximum daily dose is 250 mg/m² and the maximum total dose is 48750 mg/m², with a maximum treatment period of 260 days. This agent functions as a comparator treatment option within the physician's choice arm.

**Paclitaxel** represents another comparator option available to treating physicians. This product is formulated as a **concentrate for solution for infusion** containing paclitaxel of chemical origin as the active substance. The route of administration is **intravenous use**. The maximum daily dose amount is 225 mg/m² with a maximum total dose of 43875 mg/m² over a maximum treatment period of 260 days. Paclitaxel serves as one of the standard chemotherapy options in the treatment of physician's choice arm.

**Gemcitabine** is included as a comparator agent, supplied as a **powder for solution for infusion** containing gemcitabine of chemical origin. This medication is administered via **intravenous use**. The maximum daily dose is 2500 mg/m² and the maximum total dose is 429000 mg/m², with a maximum treatment period of 260 days. Gemcitabine may be used in combination with carboplatin as part of the physician's choice treatment regimen.

**Carboplatin** is provided as a **concentrate for solution for infusion** containing carboplatin of chemical origin as the active substance. Administration occurs via **intravenous use**. The maximum daily dose amount is 300 mg/ml with a maximum total dose of 51480 mg/ml over a maximum treatment period of 260 days. Carboplatin serves as a comparator treatment and may be administered in combination with gemcitabine according to the physician's choice.

**Capecitabine** is available as a comparator treatment option in the form of **film-coated tablets** for **oral use**. This product contains capecitabine of chemical origin as the active substance. The maximum daily dose is 6250 mg/m² with a maximum total dose of 7528125 mg/m² over a maximum treatment period of 260 days. Capecitabine represents one of the standard oral chemotherapy options available in the treatment of physician's choice arm.

**Pegfilgrastim** is utilized as an auxiliary medicinal product in this clinical trial. It is supplied as a **solution for injection** containing pegfilgrastim, a protein of other origin, as the active substance. The route of administration is **subcutaneous use**. The maximum daily dose amount is 6 mg and the maximum total dose is 515 mg, with a maximum treatment period of 260 days. Pegfilgrastim serves a supportive role in managing potential hematological complications during treatment.

Efficacy will be assessed through evaluation of progression-free survival (PFS) as determined by Blinded Independent Central Review (BICR). The primary endpoint measures the time until disease progression is detected through radiographic imaging techniques such as computed tomography scans. This assessment compares the efficacy of **izalontamab brengitecan** against treatment of physician's choice, which includes standard chemotherapy options such as **paclitaxel**, **nab-paclitaxel**, **capecitabine**, or **carboplatin** plus **gemcitabine**. Disease assessment will be conducted according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), with measurable disease evaluated by computed tomography or magnetic resonance imaging. Additionally, overall survival will be evaluated as a secondary endpoint to determine whether participants receiving **izalontamab brengitecan** demonstrate improved survival duration compared to those receiving physician's choice chemotherapy regimens.