GSK3174998 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors (ENGAGE-1)

Inclusion Criteria

• Provide signed, written informed consent.
• Male and female participants, age >=18 years (at the time consent is obtained).
• Histological documentation of locally advanced, recurrent or metastatic solid malignancy that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Participants should not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Participants whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority approved appropriate targeted therapy for their tumor types before enrollment.
• Participants with the following solid tumors are eligible for screening: Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), Renal cell carcinoma (RCC), melanoma, bladder, Soft Tissue Sarcoma (STS), Triple-negative breast cancer (TNBC), and Colorectal carcinoma displaying high microsatellite instability (MSI CRC). In Part 2B (Cohort Expansion), specific subgroups of the above solid tumors will be studied. These subgroups may be defined by specific lines of treatment, types of prior treatment, histological subtypes, and may be enriched for selected biomarkers or participant characteristics. Populations to be studied in Amendment 3 include but are not limited to the following. Enrolment of additional populations will be communicated in writing: Participants with dedifferentiated liposarcoma who have not received prior treatment with a Programmed death ligand 1 (PD-L1) inhibitor; Participants with melanoma who have received a prior PD-L1 inhibitor, had a CR, PR or SD and subsequently progressed while on PD-L1 therapy. Participants who have received prior treatment with a PD-L1 inhibitor must have documented disease progression as defined by meeting all of the following criteria: Has received at least 2 doses of an approved PD-L1 inhibitor; has demonstrated disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD , in the absence of rapid clinical progression; Progressive disease has been documented within 18 weeks from the last dose of the PD-L1 inhibitor.
• In Parts 1A and 2A, a biopsy of the tumor tissue obtained at anytime from the initial diagnosis to study entry. Although a fresh biopsy obtained during screening is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy.

Participants enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts or in Part 2B of the study must provide a fresh biopsy of a tumor lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy. In addition, an archived tumor tissue should be submitted for Participants in Part 2B, if available. The criterion for collection of fresh biopsies may be waived once GlaxoSmithKline (GSK)has determined an appropriate number of viable tissue samples have been analyzed For Part 1B and Part 2B, any archival tumor specimen must have been obtained within 3 months of starting study drug.

• Measurable disease as per RECIST v1.1
• Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Life expectancy of at least 12 weeks.
• Adequate organ function as defined by System Laboratory Values; Hematologic (Absolute neutrophil count [ANC] >=1.5x10^9/ liter [L], Lymphocyte count >=800/cubic millimeter [mm^3], Hemoglobin >=9 grams/deciliter [g/dL], Platelets >=100x10^9/L), Hepatic (Total bilirubin 50 m