A Phase III, Randomized, Open-Label, Multicenter, Global Study of Puxitatug Samrotecan (AZD8205) Monotherapy versus Physician’s Choice of Chemotherapy in Participants with B7-H4-Selected Advanced/Metastatic Endometrial Cancer Who Progressed On or After Platinum-Based Chemotherapy and Anti-PD-1/Anti-PD-L1 Therapy (Bluestar-Endometrial01)

The primary objective of this study is to evaluate progression-free survival (PFS) and overall survival (OS) comparing Arm A versus Arm B in patients with B7-H4-selected advanced/metastatic endometrial cancer who have progressed on or after platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapy. These endpoints are clinically relevant as they assess both the time to disease progression and long-term survival outcomes in this heavily pretreated patient population with limited therapeutic options.

The secondary objectives include:

• Assessment of overall response rate (ORR) for Arm A versus Arm B.

• Assessment of duration of response (DoR) for Arm A versus Arm B.

• Assessment of progression-free survival 2 (PFS2) for Arm A versus Arm B.

• Time until first subsequent anticancer therapy after discontinuation of the randomized treatment, or death (TFST) for Arm A versus Arm B.

• Time until the second subsequent anticancer therapy after discontinuation of the first subsequent treatment, or death (TSST) for Arm A versus Arm B.

• Time until discontinuation of treatment for any reason, or death (TDT) for Arm A versus Arm B.

• Worsening in endometrial symptoms for Arm A versus Arm B.

The clinical trial enrolled a total of **514 participants**, all of whom were **female**. The study population consisted of **adults** and **elderly** individuals diagnosed with **B7-H4-Selected Advanced/Metastatic Endometrial Cancer**. Participants were selected based on specific clinical characteristics, including histologically confirmed diagnosis of **endometrial carcinoma** or **carcinosarcoma** with radiological or objective evidence of **recurrence** or **progression**. All enrolled subjects had previously received **platinum-based chemotherapy** and **anti-programmed cell death 1 protein (PD-1)/anti-programmed cell death ligand 1 (PD-L1) therapy**, either as separate treatments or in combination. Participants were required to have a **WHO/ECOG performance status** of 0 or 1 at screening and radiographically measurable disease according to **RECIST 1.1** criteria. The trial population represented patients with previously treated advanced or metastatic disease who had experienced disease progression despite standard therapeutic interventions.

This is a Phase III, randomized, open-label, multicenter, global clinical trial evaluating the efficacy and safety of puxitatug samrotecan (AZD8205) monotherapy compared with physician's choice of chemotherapy in participants with B7-H4-selected advanced/metastatic endometrial cancer who have progressed on or after platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapy. The study employs a comparative design where participants are allocated to receive either the investigational biological agent AZD8205 administered as a solution for infusion via intravenous route, or standard chemotherapy options selected by the treating physician, which may include paclitaxel or doxorubicin, both administered intravenously. The trial is designed to assess multiple efficacy endpoints with the co-primary objectives of evaluating progression-free survival (PFS) and overall survival (OS) between the two treatment arms.

Eligible participants must have histologically confirmed diagnosis of endometrial carcinoma or carcinosarcoma with radiological or objective evidence of recurrence or progression. Additional key inclusion criteria require prior treatment with platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapy, either separately or in combination, a WHO/ECOG performance status of 0 or 1 at screening, and radiographically measurable disease according to RECIST 1.1 criteria. The primary endpoints include PFS defined as the time from randomization until progression per RECIST 1.1 as assessed by blinded independent central review (BICR) or death due to any cause, and OS defined as the time from randomization until death from any cause. Secondary endpoints encompass objective response rate (ORR), duration of response (DoR), PFS2, time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), time to discontinuation of treatment (TDT), and time to worsening of endometrial symptoms, physical functioning, and health-related quality of life based on select items from the EORTC QLQ-EN24.

The maximum treatment period for AZD8205 is 36 weeks with a maximum daily dose of 2.4 mg/kg and a maximum total dose of 124.8 mg/kg. For the comparator chemotherapy agents, paclitaxel may be administered at a maximum daily dose of 80 mg/m² up to a maximum total dose of 1440 mg/m² over a treatment period of up to 24 weeks, while doxorubicin may be administered at a maximum daily dose of 60 mg/m² up to a maximum total dose of 500 mg/m² over a treatment period of up to 24 weeks. The investigational product AZD8205 is supplied as a lyophilized product for concentrate for solution for infusion in amber vials, requiring reconstitution with an intravenous bag protectant containing citric acid, sodium citrate dihydrate, and polysorbate 80 to ensure compatibility with administration components.

The estimated recruitment start date for this trial is December 15, 2025, with an estimated study completion date of July 17, 2029, indicating an overall trial duration of approximately 43 months. Participants will undergo screening procedures to confirm eligibility, including assessment of B7-H4 expression status, performance status evaluation, and radiographic disease assessment. Following randomization, participants will receive their assigned treatment according to the study protocol with regular monitoring visits scheduled to assess disease response, safety parameters, and quality of life measures. Disease assessments will be conducted at predetermined intervals using RECIST 1.1 criteria with both investigator and blinded independent central review evaluations. Treatment will continue until disease progression, unacceptable toxicity, participant withdrawal of consent, or other protocol-specified discontinuation criteria are met. Participants who discontinue study treatment will enter a follow-up phase for survival monitoring and assessment of subsequent anticancer therapies. Early termination from the study may occur due to disease progression, unacceptable adverse events, participant decision to withdraw, investigator decision based on participant's best interest, pregnancy, or protocol non-compliance.

The experimental treatment in this clinical trial is puxitatug samrotecan (AZD8205), which is administered as a solution for infusion. The active substance is AZD8205, a biological product of protein origin. The drug product is presented as a lyophilized product for concentrate for solution for infusion in a 20R amber vial. The preparation of AZD8205 doses requires the use of an intravenous bag protectant to ensure compatibility with the IV bag and administration components. The intravenous bag protectant is supplied as a vial containing citric acid, sodium citrate dihydrate, and polysorbate 80. AZD8205 is administered via intravenous infusion at a maximum daily dose of 2.4 mg/kg. The maximum total dose amount is 124.8 mg/kg over a maximum treatment period of 36 months.

Paclitaxel is used as a comparator treatment in this study and is classified as a chemical medicinal product. It is provided as a concentrate for solution for infusion containing paclitaxel as the active substance. Paclitaxel is administered via the intravenous route. The maximum daily dose is 80 mg/m². The maximum total dose amount is 1440 mg/m² over a maximum treatment period of 24 weeks.

Doxorubicin serves as an additional comparator treatment option within the physician's choice of chemotherapy arm. This chemical medicinal product is supplied as a solution for injection with doxorubicin as the active substance. Administration is performed via the intravenous route. The maximum daily dose is 60 mg/m². The maximum total dose amount is 500 mg/m² over a maximum treatment period of 24 weeks.

Efficacy will be assessed using Progression Free Survival (PFS) and Overall Survival (OS) as primary endpoints. PFS is defined as the time from randomization until progression per RECIST 1.1 as assessed by blinded independent central review or death due to any cause. OS is defined as the time from randomization until the date of death due to any cause.

Secondary efficacy endpoints include Objective Response Rate (ORR), defined as the proportion of participants who have a response of complete response or partial response as determined by blinded independent central review assessments per RECIST 1.1. Duration of Response (DoR) will be defined as the time from the date of first documented response until the date of documented progression per RECIST 1.1 as assessed by blinded independent central review or death due to any cause. Additional secondary endpoints include PFS2, defined as the time from randomization to the earliest of the progression event following the initial investigator-assessed progression after first subsequent therapy or death. Time to First Subsequent Therapy (TFST) is defined as the time from randomization until the start date of the first subsequent anticancer therapy after discontinuation of the randomized treatment or death due to any cause. Time to Second Subsequent Therapy (TSST) is defined as the time from randomization until the start date of the second subsequent anticancer therapy after discontinuation of the first subsequent treatment or death due to any cause. Time to Discontinuation of Treatment (TDT) is defined as the time from randomization until discontinuation of treatment for any reason, including disease progression, toxicity, and death. Time to worsening is defined as time from date of randomization to the date of worsening while on treatment for endometrial symptoms, physical functioning, and health-related quality of life based on select items from the EORTC QLQ-EN24.