A Phase I, Open-Label Study of GSK3174998 Administered Alone and in Combination with Anticancer Agents including Pembrolizumab in Subjects with Selected Advanced Solid Tumors

Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Provide signed, written informed consent.;2. Male and female subjects, age 18 years (at the time consent is obtained).;3. 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 (with the possible exception of the PD-(L)1 naive populations described in inclusion criterion 4). Subjects should not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Subjects 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.;4. Subjects with the following solid tumors are eligible for screening: NSCLC, SCCHN, RCC, melanoma, bladder, STS, TNBC, and 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 patient 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.
- Subjects with dedifferentiated liposarcoma who have not received prior treatment with a PD-(L)1 inhibitor
- Subjects with melanoma who have received a prior PD-(L)1 inhibitor, had a CR, PR or SD and subsequently progressed while on PD-(L)1 therapy. Subjects who have received prior treatment with a PD-(L)1 inhibitor must have documented disease progression as defined by meeting all of the following criteria:
o Has received at least 2 doses of an approved PD-(L)1 inhibitor
o Has demonstrated disease progression as defined by RECIST v1.1. 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.
o Progressive disease has been documented within 18 weeks from the last dose of the PD-(L)1 inhibitor.;5. 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.
Subjects enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts or in Part 2B of the study must provide a fresh biopsy of a tumour 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 subjects in Part 2B, if available. The criterion for collection of fresh biopsies may be waived once GSK has determined an appropriate number of viable tissue samples have been analysed.;6. Measurable disease per RECIST version 1.1 - please refer to Appendix 5 of the Study Protocol. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.;7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.;8. Life expectancy of at least 12 weeks.;9. Adequate organ function (see Table 7 of study protocol, p46).;10. QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 msec or QTcF <480 msec for subjects with bundle branch block. The QTcF is the QT interval corrected for heart rate according to Fridericia's formula, machine-read or manually over-read.;11. In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.;12. Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin (*-hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
- Pre-menopausal females with one of the following:
- Documented tubal ligation
- Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
- Hysterectomy
- Documented Bilateral Oophorectomy
- Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)].;*For the complete remaining inclusion criteria, please see study protocol p53-54.*

A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Prior treatment with the following agents (from last dose of prior treatment to first dose of GSK3174998):
- TNFR agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at any time.
NOTE: Subjects treated in Part 1/monotherapy with GSK3174998 may be enrolled into Part 2/combination with pembrolizumab upon disease progression and upon discussion and approval from the GSK Medical Monitor.;- Checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors: within 4 weeks.NOTE: Subjects entering the PD-(L)1 naive expansion cohort may not have received any prior PD-(L)1 anti-cancer treatment.
- 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 one unirradiated measurable lesion is available for assessment via RECIST version 1.1. A wash out of at least two weeks before start of study drug for palliative radiation to the extremities for osseous bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is required.
- Investigational therapy: if the subject has participated in a clinical trial and has received an investigational product: within 30 days or 5 halflives of the investigational product (whichever is shorter). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug. Note: if the agent is a TNFR agonist or a checkpoint inhibitor, the above exclusions take precedence.;2. Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.;3. Toxicity from previous treatment:
- Subjects with *Grade 3 toxicity related to prior immunotherapy leading to study treatment discontinuation are not eligible.
- Subjects whose toxicity related to prior treatment has not resolved to * Grade 1 (except alopecia, hearing loss, grade * 2 neuropathy or endocrinopathy managed with replacement therapy) are not eligible.;4. Malignancy other than disease under study, except as noted below:
- Any other malignancy from which the subject has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on currently targeted malignancy, can be included in this clinical trial.;5. Central nervous system (CNS) metastases, with the following exception:
- Subjects who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids for 2 weeks prior to first dose of study drug.
Note: Subjects with carcinomatous meningitis are excluded regardless of clinical stability.;6. Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colonystimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GMCSF], recombinant erythropoietin) within 2
weeks before the first dose of study drug.;7. Major surgery * 4 weeks before the first dose of study treatment. Subjects must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.;8. Active autoimmune disease (see Appendix 2) that has required systemic treatment within the last 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.;9. Concurrent medical condition requiring the use of systemic immunosuppressive medications within 28 days before the first dose of study treatment. 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 subject is on a stable dose.;10. Active infection, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.;11. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.;12. Known, current drug or alcohol abuse.;*For the complete reminaining exclusion criteria, please see study protocol p56.*