This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed
to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and
preliminary clinical activity of GSK3174998 administered intravenously to subjects with
selected advanced or recurrent solid tumors.
This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy
(Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with
The study will be conducted in 2 parts, each part consisting of a dose-escalation phase
followed by a cohort expansion phase. Part 1 will evaluate GSK3174998 monotherapy, while
Part 2 will evaluate GSK3174998 in combination with pembrolizumab.
GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of
GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic
activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be
evaluated with fixed doses of pembrolizumab.
The study will enroll up to approximately 180 subjects with different tumor types
(approximately 60 subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects
in Parts 1B and 2B [cohort expansion]). The maximum duration of treatment with GSK3174998
will be 48 weeks; the maximum duration of treatment with pembrolizumab will be 2 years. The
follow-up period for safety assessments will be a minimum of 3 months from the date of the
last dose. The post-treatment follow-up period includes disease assessments every 12 weeks.
- Provide signed, written informed consent.
- Male and female subjects, 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. 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.
- Subjects 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 microsatellite instability (MSI
- 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. 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 Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1. 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 >1,000/cubic
millimeter [mm^3], Hemoglobin >=9 grams/deciliter [g/dL], Platelets >=100x10^9/L),
Hepatic (Total bilirubin <=1.5x upper limit of normal [ULN] [For subjects with
Gilbert's Syndrome, only if direct bilirubin <=35%, <=3.0xULN], alanine
aminotransferase [ALT] <=1.5xULN); Renal (Serum Creatinine <=1.5xULN OR Calculated
creatinine clearance [CrCl >50 mL/min) and Endocrine (Thyroid stimulating hormone
[TSH] within normal limits. If TSH is not within normal limits at baseline, the
subject may still be eligible if total T3 or free T3 and free T4 are within the
- QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 msec or <480
milliseconds (msec) for subjects with bundle branch block.
Female subjects and male subjects with female partners of child bearing potential must
comply with adequate contraception requirements from the time of first dose of study
medication until 120 days after the last dose of study medication.
- Prior treatment with the following agents (from last dose of prior treatment to first
dose of GSK3174998): Tumor necrosis factor receptor (TNFR) agonists, including OX40,
CD27, CD137 (4-1BB), CD357 (GITR): at any time; Checkpoint inhibitors, including
PD-1, PD-L1, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors: within 8
- Prior allogeneic or autologous bone marrow transplantation or other solid organ
- Active residual toxicity from prior therapies.
- Secondary malignancy.
- Brain metastases.
- Active autoimmune disease that has required systemic treatment within the last 2
- Active infection, known human immunodeficiency virus infection, or positive test for
hepatitis B surface antigen or hepatitis C.
- Current active liver or biliary disease.
- Acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or
gastrointestinal obstruction within the past 6 months.
- Severe hypersensitivity to other monoclonal antibodies (mAbs).
- Recent (within 6 months) history of second degree (Type II) or third degree
atrioventricular (AV) block cardiomyopathy, myocardial infarction, acute coronary
syndromes (including unstable angina), coronary angioplasty, stenting, or bypass
grafting; Class II, III, or IV heart failure, or symptomatic pericarditis.
- History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung disease, or
organizing pneumonia, or evidence of active, non-infectious pneumonitis.
- Uncontrolled symptomatic ascites or pleural effusions within 6 months.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Part 1 and 2: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)
Part 1A and 2A: Dose limiting toxicities (DLT)
Part 1 and 2: Number of withdrawals due to AEs
Part 1 and 2: Number of dose reductions or delays
Part 1 and 2: Change in composite of clinical laboratory assessments as a measure of safety, including hematology, clinical chemistry, thyroid functions and urinalysis parameters
Part 1 and 2: Change in composite of vital signs as a measure of safety, including temperature, systolic and diastolic blood pressure, and pulse rate
Part 1 and 2: Changes in electrocardiogram (ECG) as a measure of safety
Part 1 and 2: Objective response rate (ORR)
Part 1 and 2: Disease Control Rate (DCR)
Part 1 and 2: Time to response
Part 1 and 2: Overall survival (OS)
Part 1 and 2: Duration of Response (DoR)
Part 1 and 2: Progression Free Survival (PFS)
Part 1: Pharmacodynamic activity of GSK3174998 in tissue and periphery
Part 2: Pharmacodynamic activity of GSK3174998 in combination with pembrolizumab in tissue and periphery
Part 1 and 2: Number and percentage of subjects who develop detectable antidrug antibodies (ADA) against GSK3174998
Part 2 only: Number and percentage of subjects who develop detectable ADA against Pembrolizumab
Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - tmax, terminal phase half life
Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - AUC
Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - terminal phase rate constant
Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - clearance
Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - Cmax and Cmin