MC# 22-03

1. Provide signed informed consent.  Participant must be capable of providing informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Participants ≥18 years of age at the time of signing the ICF
3. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
   1. Is not a woman of childbearing potential (WOCBP) as defined in Section 10.4.1: Contraception and Barrier Guidance OR
   2. Is a WOCBP and using a contraceptive method that is highly effective with a failure rate of <1% per year), preferably with low user dependency, as described in Section 10.4.2 during the intervention period and for at least 15 weeks after the last dose of GSK4381562 and 120 days after the last dose of dostarlimam.  The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
   3. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24-48 hours before the first dose of study intervention
      1. 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.
   4. Additional requirements for pregnancy testing during and after study intervention are located in Section 8.2.6
   5. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
4. Histological or cytological documentation of loco-regionally recurrent solid tumors or metastatic solid tumors; types as follows:
   1. head and neck squamous cell carcinoma (HNSCC)
   2. non-small-cell lung cancer (NSCLC)
   3.  breast cancer (BC)
   4. clear cell renal cell cancer (ccRCC)
   5. gastric cancer (GC)
   6. colorectal cancer (CRC)
   7. endometrial cancer (EC)
   8. ovarian epithelial cancer (OEC)
5. Disease that has progressed after standard therapy for the specific tumor type, for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists
   1. Measurable disease per RECIST 1.1
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
7. Life expectancy of at least 12 weeks
8. Adequate organ function, as defined in Table 7

Abbreviations: ALT = alanine aminotransferase; ANC = Absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; GFR = glomerular filtration rate; INR = international normalized ratio; MUGA = multigated acquisition; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal;

a. Hematologic criteria must be met without transfusion of blood products (including platelets or red blood cells) or initiation of G-CSF for at least 14 days prior to sample collection

b. eGFR to be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula

c. MUGA scan is acceptable if echocardiography is not standard practice at the investigational site

1. Prior treatment with the following therapies (specified time periods are from last dose of prior treatment to first dose of GSK4381562):
   1. Any therapy directed against PVRIG (eg. COM701 or other anti-PVRIG mAb) or other CD226 axis receptor (TIGIT or CD96) at any time
   2. Immune-checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors, within 4 weeks
   3. Other anticancer therapy, including chemotherapy, targeted therapy, and biological therapy: within 4 weeks or 5 half-lives of the drug, whichever is shorter.  Prior radiation therapy is permissible if at least 1 nonirradiated measurable lesion is available for assessment via RECIST 1.1.  A washout between radiation and the start of study intervention is required as follows: 1) at least 2 weeks for radiation with palliative intent or ≤50Gy total dose; 2) at least 4 weeks for high dose radiation (>50Gy total dose).
   4. Investigational therapy: if the participant has participated in a clinical study and has received an investigational product within 4 weeks or 5 half-lives of the investigational product (whichever is shorter)
2. Prior allogenic or autologous bone marrow transplantation or other solid organ transplantation
3. Toxicity from previous anticancer treatment, including
   1. ≥Grade 3 immune-mediated toxicity considered related to prior immunotherapy and that led to treatment discontinuation; or
   2. Toxicity related to prior treatment that has not resolved to ≤Grade 1. Non clinically relevant Grade 2 toxicities, not constituting a safety risk by investigator judgment are allowed
4. Participant has a known additional malignancy that progressed or required active treatment within the last 2 years.  Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included only after approval from the medical monitor.
5. Participants with any carcinomatous meningitis or leptomeningeal spread and those with uncontrolled or symptomatic central nervous system (CNS) metastases
   • Note: Participants with previously treated brain metastases may participate provided they are asymptomatic (any neurologic symptoms have returned to baseline [participants may be receiving stable doses of anticonvulsants]), radiographically stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 2 weeks prior to study treatment
6. Active autoimmune disease that has required systemic disease-modifying or immunosuppressive treatment within the last 2 years.  (Note: Stable, medically managed autoimmune endocrinopathies are acceptable if participant otherwise meets entry criteria.)
7. Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study intervention.  Physiologic doses of corticosteroids for treatment of endocrinopathies or steroids with minimal systemic absorption, including topical, inhaled, or intranasal corticosteroids may be continued if the participant is on a stable dose.  (Note: Corticosteroid premedication for contrast allergy is permitted.)
8. Cirrhosis or current unstable liver or biliary disease, defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice.  Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
9. Active infection requiring systemic treatment, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).  Participants who test positive for HCV antibodies are eligible if HCV RNA is undetectable.
10. QTcF >470 msec, or >480 msec for participants with bundle branch block.  QTcF is QT corrected for heart rate according to Fridericia’s formula and can be machine calculated or manually over-read.
11. Allergen desensitization therapy within 4 weeks of starting study intervention
12. History of hypersensitivity to mAbs. For Arm B, history of hypersensitivity to dostarlimab or its excipients
13. History or evidence of cardiovascular (CV) risk including any of the following:
    1. Recent history (within 6 months) of serious uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities including second degree (Type II) or third-degree atrioventricular block
    2. Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within 6 months
    3. Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association Functional Classification System [The Criteria Committee of the New York Heart Association, 1994] (Appendix 9)
    4. Recent history (within 6 months) of symptomatic myocarditis or pericarditis
14. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions
15. History of idiopathic pulmonary fibrosis; interstitial lung disease; organizing pneumonia; noninfectious pneumonitis that required steroids, or evidence of active, noninfectious pneumonitis.  (Note: postradiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation induced pneumonitis not requiring treatment may be permitted if agreed by investigator and sponsor.)
16. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the participant’s safety, obtaining informed consent, or compliance with the study procedures
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is study site or sponsor staff directly involved with this study, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific participant
18. Receipt of live vaccine within 30 days of the start of study intervention
19. Receipt of any COVID-19 vaccine within 14 days of the first dose of study intervention
20. Receipt of transfusion of blood products (including platelets or red blood cells) or initiation of colony-stimulating factors (including granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, and recombinant erythropoietin) within 14 days before the first dose of study intervention
21. Major surgery less than 4 weeks before the first dose of study intervention.  Participants must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study intervention.
22. Known current or ongoing drug or alcohol abuse