A Study of Mocertatug Rezetecan in Combination With Anti-cancer Therapies for Advanced Solid Tumors (BEHOLD-2)

Inclusion Criteria:

* Participants must be 18 years of age inclusive or older, at the time of signing the informed consent, or the legal age of consent in the jurisdiction in which the study is taking place.
* Participant capable of giving signed informed consent including compliance with the requirements and restrictions listed in the Informed consent form (ICF) and in this protocol.
* Participants with pathologically confirmed advanced solid tumor specific for study Module (key local diagnostic molecular and/or immunophenotyping testing results/tumor cell phenotype results for confirmed diagnosis should be provided) with no more than 4 lines of prior systemic therapies. Please note:

  1. Adjuvant +/- neoadjuvant considered one line of therapy
  2. Maintenance therapy will be considered as part of the preceding line of therapy (i.e., not counted independently)
  3. Unplanned addition or switching to a new drug in a different class is considered a separate line of therapy. If an agent in a regimen is switched to another agent in the same class due to toxicity or intolerance (e.g. hypersensitivity reaction) this is considered part of the same line (i.e. not counted independently).
* Requirements for tumor tissue samples: Archival or fresh tumor tissue is required for retrospective central assessment of B7H4 expression by immunohistochemistry (IHC) and other biomarker analysis. The archival tumor tissue should be from the most recent procedure (ideally obtained after the last anti-cancer treatment). If an archival tissue is not available a new biopsy should be performed, and the newly obtained tissue provided.
* Participants have at least one target lesion as assessed per RECIST 1.1. A target lesion is defined as a measurable lesion that has not undergone locoregional treatment such as irradiation or that has unequivocal progression following locoregional treatment, with the longest diameter of ≥ 10 millimeter (mm) at Baseline (for lymph node lesions, the short axis should be ≥ 15 mm).
* Participants have a life expectancy of at least 12 weeks per investigator assessment based on disease burden and extent of supportive care needed.

Inclusion criteria of participants under arm Module 1 (Mo-Rez +Dostarlimab) Endometrial Cancer Part 1A:

a. Participants with histologically documented, advanced (metastatic and/or unresectable) or recurrent endometrial cancer who have failed in adequate standard treatments, do not have effective standard treatment or are intolerant to standard of care, and who are not candidates for further curative external radiotherapy or brachytherapy.

Inclusion criteria of participants under arm Module 1 (Mo-Rez +Dostarlimab) Endometrial Cancer Part 1B:

1. Diagnosis of endometrial cancer with confirmed mismatch repair proficient (MMRp) or microsatellites stable (MSS) tumor status by local test.
2. Participants who have progressed on or are intolerant to at least 1 line of standard prior systemic therapy (including neoadjuvant or adjuvant as prior line), and who are not candidates for curative external radiotherapy or brachytherapy. Maintenance therapy will be considered part of the preceding line of therapy (i.e, not counted independently).

Inclusion criteria of participants under arm Module 2 (Mo-Rez +/- Bevacizumab) Ovarian Cancer Part 2A:

a. Participants with histologically or cytologically confirmed advanced epithelial ovarian cancer/fallopian tube/peritoneal cancer (any epithelial histology - mucinous, clear cell, carcinosarcoma, high/low grade serous, endometrioid) who have failed in adequate standard treatments, do not have effective standard treatment or are intolerant to standard of care.

Inclusion criteria of participants under arm Module 2 (GSK5733584 +/- Bevacizumab) Ovarian Cancer Part 2B:

1. Participants whose advanced ovarian cancer/fallopian tube/peritoneal cancer has relapsed more than 6 months from the last dose of platinum before enrollment, i.e., platinum sensitive.
2. Participants who have progressed on or are intolerant to at least 1 line of standard prior lines of chemotherapy and are not candidates for second cytoreductive surgery.

   * Participants willing to use adequate contraception.

Female participants:

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

* Is a Woman of non-childbearing potential (WONCBP) OR
* Is a Woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective.
* A WOCBP 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

  * Has an ECOG performance status of 0 to 1.
  * Participants with normal organ and bone marrow function.

Exclusion Criteria:

* Has a second malignancy (except disease under study) that has progressed or required active treatment within the past 24 months 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.
* Has had any major surgery within 28 days prior to enrolment.
* Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.
* Has known sensitivity to study intervention components, Mo-Rez (antibody-drug conjugate, antibody, free cytotoxin GSK5757810A) and combination partner, or its excipients or other allergy that, in the opinion of the investigator, contraindicates participation in the study.
* Has any following cardiological examination abnormality:

  1. history in prior year of clinically significant or uncontrolled cardiac disease, acute myocardial infarction, NYHA Class III or IV congestive heart failure or clinically significant arrhythmia not controlled by standard of care therapy.
  2. Corrected QT Interval (QTcF) \>450 millisecond (msec) or QTcF \>480 msec for participants with bundle branch block
* Has untreated brain or CNS metastases or brain/CNS metastases rapidly progressing requiring urgent medical intervention.
* Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or non-infectious pneumonitis.
* Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary).
* Clinically significant bleeding symptoms, significant bleeding tendency, or bleeding tumors within 1 month prior to the first dose of study treatment.
* Serious or poorly controlled hypertension, including history of hypertensive crisis, hypertensive encephalopathy; adjustment of antihypertensive medications due to poor blood pressure control within 2 weeks prior to the first dose of study treatment;
* Has any active renal condition (e.g., infection, requirement for dialysis, or any other active significant renal condition or dehydrated condition that could affect the participant's safety). Note: renal obstruction successfully managed by stenting is permitted.
* Has any serious and/or unstable medical condition (such as clinical symptoms of intestinal obstruction) or 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.
* Participants with known history of Human immunodeficiency virus (HIV).

Exclusion criteria of participants under arm Module 1 (Mo-Rez +Dostarlimab) Endometrial Cancer:

1. Has mesenchymal tumor of the uterus (uterine sarcoma).
2. Has experienced symptomatic pericarditis of any etiology within 6 months of study treatment or any of the following with prior immunotherapy: any imAE ≥ Grade 3, immune-mediated severe neurologic events of any-grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (SJS, TEN, or DRESS syndrome), or myocarditis of any grade.

Exclusion criteria of participants under arm Module 2 (Mo-Rez +/-Bevacizumab) Ovarian Cancer:

1. Participants with wound healing complications or incompletely healed wounds.
2. Participants with history or evidence of gastrointestinal perforation, tracheoesophageal fistula, or any grade 4 fistula; participants with gastrointestinal fistula, visceral fistula, or abdominal abscess within 6 months prior to the first dose, participants with history of osteonecrosis of the jaw.
3. Participants who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
4. Participants with congenital bleeding diathesis, acquired coagulopathy, recent pulmonary haemorrhage/ haemoptysis (\> 2.5 mL of red blood or ½ teaspoon) within the last 3 months. Participants receiving treatment for thromboembolism are permitted as long as they have been on a stable dose of anticoagulation for at least 1 month.
5. Participant has history of congestive heart failure (CHF) or baseline LVEF \<50% or institutional lower limits of normal.
6. Participant with history of nephrotic syndrome or grade 3 proteinuria. Participants has proteinuria as demonstrated by urine dipstick for proteinuria ≥2 (participants discovered to have ≥2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate ≤1 g of protein in 24 hours to be eligible).

   * Has an Alanine transaminase (ALT) value \>2.5x Upper Limit of Normal (ULN) and for participants with documented liver metastases/tumor infiltration has an ALT value \>5x ULN.
   * Has a total bilirubin value \>1.5x ULN.
   * Has documented presence of HBsAg and/or HBcAb, or HBsAb (except for presence of HBsAb attributable to previous vaccination) at screening or within 3 months prior to the first dose of study intervention.
   * Has a positive HCV antibody test result at screening or within 3 months prior to the first dose of study intervention.
   * Has received prior therapy with topoisomerase-1 inhibitors or ADC with topoisomerase-1 inhibitor warhead, or B7H4 targeted therapy.
   * Has received treatment with any cytotoxic chemotherapy drugs or other anti-tumor drugs (including endocrine therapy, molecular targeted therapy, immunotherapy, biotherapy, and investigational drug) within 30 days or 5 half-lives, whichever is shorter of a medicinal product prior to the first dose of study drug; or need to continue these drugs during the study.
   * Use of inhibitors of P-gp, breast cancer resistance protein (BCRP) or OATP1B1/1B3 within 7 days prior to the first dose of study drug. P-gp inducers should be discontinued for at least 14 days before the start of the study.
   * Have received locoregional radiation therapy within 2 weeks prior to the first dose of study drug; more than 30% of bone marrow irradiation or wide-field radiation therapy within 4 weeks prior to the first dose of study treatment.
   * Has serious infections within 4 weeks prior to the first dose, including but not limited to infectious complications, bacteremia, severe pneumonia treated with intravenous antibiotics for ≥2 weeks.