This study specifically aims to evaluate how well mocertatug rezetecan (Mo-Rez) works in treating Endometrial Cancer (EC) compared to standard of care. The study also assesses whether Mo-Rez is safe and tolerated well by participants in comparison to standard of care and will help provide a better understanding of the main side effects of the drugs.

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Is at least 18 years of age and the legal age of consent in the jurisdiction in which the study is taking place at the time of signing the Informed consent form (ICF).

• Has histologically confirmed endometrial carcinoma including but not limited to endometroid, serous, clear cell, and endometrial carcinosarcoma. Mixed epithelial carcinomas are permitted.

• Has undergone at least 1 and no more than 2 lines of prior systemic treatment for EC. Up to 3 lines of prior systemic treatment are acceptable if one line was administered in the adjuvant/neo-adjuvant setting. The definition of prior lines of therapy is as follows:

  • Adjuvant ± neo-adjuvant therapy counts as one line of treatment.
  • Maintenance therapy is considered part of the preceding line and does not count as an independent line.
  • Switching to another agent within the same class due to toxicity (without disease progression) is considered part of the same line of therapy.
  • Unplanned addition or switching to a new anti-cancer therapy in a different class is considered a separate line of therapy.
  • Hormonal therapy is NOT counted as a separate line.

• Must have progressed on or after prior platinum-based chemotherapy and have received anti- Programmed cell death 1 (PD-1) /anti- Programmed cell death ligand 1 (PD-L1) therapy, either separately or in combination. Participants deemed unsuitable for a prior PD-1/PD-L1 inhibitor therapy (contraindications such as immunodeficiency, autoimmune disease that required systemic treatment) as determined by the investigator or treating physician are eligible.

• Participants must have a platinum-free interval of less than 12 months if they previously received platinum-based therapy solely in the adjuvant setting. The platinum-free interval is defined as the date of the last dose of platinum-based chemotherapy to the date of disease progression.

  • If PD-L1/PD-1 inhibitor therapy was administered with platinum-based treatment, participant is eligible regardless of whether the Platinum-free interval (PFI) exceeds 12 months.
  • Participants with metastatic disease who underwent treatment including gynecological surgery followed by a platinum-based regimen, or those deemed intolerant to platinum-based therapy, are eligible regardless of whether the PFI exceeds 12 months.

• Has provided a Formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample sufficient for the central assessment of B7 homolog 4 protein (B7-H4) expression, with the result of B7-H4 expression testing available prior to date of randomization.

• Has ≥1 Target Lesion per RECIST 1.1 by BICR eligibility review of screening scans.

• Is willing to use adequate contraception. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies:

  • Is a Participant of non-childbearing potential (PONCBP) OR
  • Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, 30 days prior to Cycle 1 Day 1 (C1D1) and during the study intervention period and for at least 8 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.

• A POCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention

  • If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
  • Additional requirements for pregnancy testing during and after study intervention are described in protocol.
  • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a participant with an early undetected pregnancy.

• Is capable of giving signed informed consent including compliance with the requirements and restrictions listed in the ICF and in the protocol.

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Has adequate organ function.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Mesenchymal tumors of the uterus (uterine sarcomas) and neuroendocrine uterine cancer.

• Has a malignancy (except disease under study) that has progressed or required active treatment within the past 36 months prior to date of randomization except for basal cell or squamous cell carcinomas of the skin or in-situ carcinomas [e.g., breast, cervix, bladder] that have been resected with no evidence of metastatic disease, or that is otherwise considered cured by the investigator.

• Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.

• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

• Has untreated brain or Central nervous system (CNS) metastases or brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases). Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for ≥14 days before date of C1D1 are not excluded from participation.

• Has any evidence of current Interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis.

• Has ongoing adverse reaction(s) from prior therapy that has (have) not recovered to ≤ Grade 1 or to the baseline status preceding prior therapy, excluding alopecia, hearing loss, vitiligo and endocrinopathy managed with replacement therapy, or that the investigator, with the agreement of the sponsor, considers to be stable or not clinically relevant for the tolerability of study intervention in the current clinical study.

• Has any serious and/or unstable medical condition (including infection) or any serious and/or unstable psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that could interfere with the participant's safety, obtainment of informed consent, or compliance to the study procedures.

• Has had any major surgery within 28 days prior to date of C1D1 or history of local radiotherapy within 21 days prior to C1D1.

• Has received treatment with an investigational agent within 30 days prior to C1D1.

• Has received prior therapy with Topo1i (e.g. irinotecan or topotecan) or ADC with a Topo1i payload, or B7-H4 targeted therapy.

• Has received treatment with any cytotoxic chemotherapy drugs or other antitumor drugs (including endocrine therapy, molecular targeted therapy, immunotherapy, biotherapy and investigational drug) within 30 days or 5 half-lives, whichever is shorter, prior to C1D1; or need to continue these drugs during the study.

• Has received any live vaccine within 30 days prior to C1D1.Note: mRNA and adenoviral-based Coronavirus disease 2019 (COVID-19) vaccines are considered non-live.

• Has received treatment with inhibitors of P-glycoprotein (P-gp), Breast cancer resistant protein (BCRP), or OATP1B1/1B3 transporters within 7 days prior to first dose of study drug. P-gp inducers should be discontinued for at least 14 days before the start of the study drug.

• Has received any transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including Granulocyte colony stimulating factor (G-CSF), Granulocyte-macrophage colony stimulating factor (GM-CSF), or recombinant erythropoietin) within 14 days prior to C1D1.

• Has a known Human immunodeficiency virus (HIV) infection AND meets at least 1 of the following criteria:

  • Has documented evidence of plasma HIV-1 Ribonucleic acid (RNA) ≥50 c/mL within 3 months prior to or at screening. In the 3 to 12 months prior to screening, plasma HIV1 RNA levels consistently <50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥50 c/mL occurred in the 3 to 12 months prior to screening, the participant is not eligible for enrollment unless, per the investigator's assessment, the elevations were neither persistent nor associated with antiretroviral resistance; OR
  • Has not had Cluster of differentiation (CD)4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at screening); OR
  • Has had any CD4 cell count values ≤350 cells/mm3 in the past 12 months. OR
  • Has had 1 or more changes in their combination antiretroviral therapy regimen or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to screening; OR
  • Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to screening or a history of HIV-associated invasive cervical cancer; OR
  • Has received treatment with an HIV1 immunotherapeutic vaccine within 90 days prior to screening.

• Has an Alanine aminotransferase (ALT) value >2.5× Upper limit of normal (ULN) and/or for participants documented liver metastases/tumor infiltration has an ALT value >5x ULN

• Has a total bilirubin value >1.5x ULN.

• Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.

• Has documented presence of Hepatitis B surface antigen (HBsAg) and/or Hepatitis B core antibody (HBcAb) at screening unless they meet both the following criteria:

  • Participants with chronic Hepatitis B virus (HBV) infection (HBsAg+) or positive HBcAb are required to be receiving effective antiviral therapy (i.e., with nucleos(t)ide analogs [Tenofovir or Entecavir]) for at least 14 days prior to C1D1 and are willing to continue for at least 6 months after treatment discontinuation or longer at the discretion of the treating hepatologist.
  • HBV Deoxyribonucleic acid (DNA) must be adequately suppressed, as per institutional or local guidelines, prior to initiation of study intervention.

• Has a positive Hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to C1D1 unless HCV RNA is negative, indicating past resolved HCV infection, including participants who have undergone curative treatment.

• Has a positive HCV RNA test result at screening or within 3 months prior to C1D1.

• Has QTc >470 milliseconds (msec)

• Has a history within 12 months prior to screening of clinically significant or uncontrolled cardiac disease, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure [NYHA 1994], or clinically significant arrhythmia not controlled by standard of care therapy.

• Has Left ventricular ejection fraction (LVEF) <50% or less than institutional lower limit of normal.

• Has any active renal condition (e.g., infection, requirement for dialysis, or any other significant renal condition that could affect the participant's safety).

Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/gsk-patient-level-data-sharing-july2025.pdf

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months, but an extension may be granted, when justified, for up to 6 months.

The independent central reviewer assessing primary outcome data will be masked (blinded) from participants treatment assignment