A Phase III, randomized, multi-site, open-label trial of BNT323/DB-1303 versus investigator’s choice of chemotherapy in previously treated patients with HER2- expressing recurrent endometrial cancer

The primary objective is to assess the efficacy of BNT323 compared to investigator's choice of chemotherapy in terms of a hazard ratio for progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by blinded independent central review in participants with human epidermal growth factor receptor 2 (HER2)-expressing recurrent endometrial cancer and prior immune checkpoint inhibitor treatment. This primary endpoint evaluates the ability of BNT323 to delay disease progression in a specific population of patients with HER2-expressing tumors who have previously received immune checkpoint inhibitor therapy.

The secondary objectives include:

• Assessment of the efficacy of BNT323 compared to investigator's choice of chemotherapy in terms of a hazard ratio for progression-free survival according to RECIST 1.1 assessed by blinded independent central review in all participants with HER2-expressing recurrent endometrial cancer.

• Assessment of the efficacy of BNT323 followed by any other subsequent anticancer therapy compared to investigator's choice of chemotherapy followed by any other subsequent anti-cancer therapy in terms of a hazard ratio for overall survival in participants with HER2-expressing recurrent endometrial cancer and with prior immune checkpoint inhibitor treatment.

• Assessment of the efficacy of BNT323 followed by any other subsequent anticancer therapy compared to investigator's choice of chemotherapy followed by any other subsequent anti-cancer therapy in terms of a hazard ratio for overall survival in all participants with HER2-expressing recurrent endometrial cancer.

• Assessment of the efficacy of BNT323 compared to investigator's choice of chemotherapy in terms of progression-free survival according to RECIST 1.1 assessed by the investigator in participants with prior immune checkpoint inhibitor treatment and in all participants.

• Assessment of the anti-tumor activity of BNT323 compared to investigator's choice of chemotherapy in terms of objective response rate and duration of response according to RECIST 1.1 assessed by blinded independent central review and the investigator in participants with prior immune checkpoint inhibitor treatment and in all participants.

• Assessment of the safety and tolerability profile of BNT323 and investigator's choice of chemotherapy.

The clinical trial enrolled a total of **291 participants**, all of whom were **female adults**. The study population consisted of individuals diagnosed with **histologically confirmed endometrial cancer** that was **recurrent** and expressed **human epidermal growth factor receptor 2 (HER2)** with an immunohistochemistry score of 1+, 2+, or 3+, excluding true sarcomas. Participants were required to have **measurable disease** according to **Response Evaluation Criteria in Solid Tumors (RECIST) 1.1** and an **Eastern Cooperative Oncology Group (ECOG) Performance Status** of 0, 1, or 2. The trial included patients who had received at least one prior line of **platinum-based therapy** in any treatment setting, with a maximum of three prior lines of therapy permitted. All participants were required to have a **life expectancy** of 12 weeks or longer at the time of screening. The trial population was selected based on these specific clinical characteristics to evaluate the efficacy of the investigational treatment compared to standard chemotherapy options.

This is a **Phase III**, **randomized**, multi-site, **open-label** clinical trial evaluating the efficacy and safety of **BNT323** (DB-1303) compared to investigator's choice of **chemotherapy** in participants with **HER2-expressing** recurrent **endometrial cancer** who have received prior treatment. The trial investigates BNT323, administered as a **powder for concentrate for solution for infusion** via **intravenous infusion**, against two chemotherapy comparators: **doxorubicin hydrochloride** administered as a **solution for injection**, and **paclitaxel** administered as a **solution for infusion** via **intravenous infusion**. The maximum treatment period for all investigational products is **6 months**. BNT323 is administered at a maximum daily dose of **8 mg/kg** with a maximum total dose of **72 mg/kg**. Doxorubicin hydrochloride is administered at a maximum daily dose of **60 mg/m²** with a maximum total dose of **540 mg/m²**. Paclitaxel is administered at a maximum daily dose of **80 mg/m²** with a maximum total dose of **1600 mg/m²**.

The primary objective of the trial is to assess the efficacy of BNT323 compared to investigator's choice of chemotherapy in terms of a **hazard ratio** for **progression-free survival** according to **Response Evaluation Criteria in Solid Tumors** (RECIST) 1.1 assessed by **blinded independent central review** (BICR) in participants with **human epidermal growth factor receptor 2** (HER2)-expressing recurrent endometrial cancer and prior **immune checkpoint inhibitor** (ICI) treatment. The **primary endpoint** is progression-free survival by BICR, defined as the time from randomization to the first objective tumor progression per RECIST 1.1 or death from any cause, whichever occurs first. **Secondary endpoints** include progression-free survival by BICR, **overall survival** defined as the time from randomization to death from any cause, progression-free survival assessed by the investigator, **objective response rate** defined as the proportion of participants with **complete response** or **partial response** per RECIST 1.1 as best overall response with confirmation, **duration of response** defined as the time from first objective response to first occurrence of objective tumor progression or death from any cause, occurrence of **treatment-emergent adverse events** including Grade 3 or above, serious, and fatal events by relationship, and occurrences of treatment-emergent adverse events leading to drug interruption, dose reduction, or discontinuation of trial treatment.

Eligible participants are female adults with histologically confirmed endometrial cancer that is recurrent, has a **HER2 IHC score** of 1+, 2+, or 3+ as determined by central laboratory testing for HER2 protein expression, and is not defined as a true sarcoma. Participants must have **measurable disease** defined by RECIST 1.1, an **Eastern Cooperative Oncology Group** (ECOG) **Performance Status** of 0, 1, or 2, and have received at least one prior line of **platinum-based therapy** in any setting, with up to three lines of prior therapy allowed. Participants must have a **life expectancy** of 12 weeks or longer at screening. The trial is expected to commence recruitment on **28 November 2025** and conclude on **15 November 2029**, representing an overall trial duration of approximately **4 years**.

The experimental treatment in this clinical trial is BNT323, which contains the active substance DB-1303. BNT323 is supplied as a powder for concentrate for solution for infusion and is administered via intravenous infusion. The dosing regimen is weight-based at a maximum daily dose of 8 milligrams per kilogram body weight. The maximum total dose administered is 72 milligrams per kilogram over a treatment period of up to 6 months. The active substance DB-1303 is classified as a protein of other origin.

The comparator treatment arm includes investigator's choice of chemotherapy, which consists of two approved chemotherapeutic agents. The first comparator is Ribodoxo 2 milligrams per milliliter solution for injection, which contains doxorubicin hydrochloride as the active substance. Ribodoxo is administered as a solution for injection at a maximum daily dose of 60 milligrams per square meter body surface area. The maximum total dose is 540 milligrams per square meter over a treatment period of up to 6 months. This product is authorized in Germany and undergoes re-packaging and re-labeling for the purposes of this clinical trial.

The second comparator option is Paclitaxel AqVida 6 milligrams per milliliter concentrate for solution for infusion, containing paclitaxel as the active substance. This medicinal product is administered via intravenous infusion at a maximum daily dose of 80 milligrams per square meter body surface area. The maximum total dose is 1600 milligrams per square meter over a treatment period of up to 6 months. Paclitaxel AqVida is authorized in Germany and also undergoes re-packaging and re-labeling for use in this trial. Both comparator chemotherapy agents are chemical substances and represent standard treatment options selected at the investigator's discretion.

Efficacy will be assessed using progression-free survival (PFS) as the primary endpoint, defined as the time from randomization to the first objective tumor progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first. PFS will be evaluated by blinded independent central review (BICR) to compare BNT323 with investigator's choice of chemotherapy in participants with HER2-expressing recurrent endometrial cancer who have received prior immune checkpoint inhibitor treatment.

Secondary efficacy endpoints include PFS assessed by BICR, overall survival (OS) defined as the time from randomization to death from any cause, and PFS assessed by the investigator. Additional secondary endpoints comprise objective response rate (ORR), defined as the proportion of participants achieving complete response or partial response per RECIST 1.1 as best overall response with confirmation, and duration of response (DoR), defined as the time from first objective response to first occurrence of objective tumor progression or death from any cause, whichever occurs first. Safety outcomes will be evaluated through the occurrence of treatment-emergent adverse events, including Grade 3 or above, serious, and fatal events, as well as events leading to drug interruption, dose reduction, or discontinuation of trial treatment.