Patient case: 49-year-old male with melanoma; genetic feature: extensive tumor infiltrating lymphocytes

Clinical trial: GSK3174998 Alone or With Pembrolizumab in Subjects With Advanced Solid Tumors (ENGAGE-1)

Summary: 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 additional therapies.
  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 264 subjects with different tumor types (approximately 144 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 plus or minus pembrolizumab will be 2 years or 35 cycles, whichever comes first. 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.


Eligibility: Inclusion Criteria:
  -  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, Triple-negative breast cancer (TNBC), and Colorectal carcinoma displaying microsatellite instability (MSI CRC).
  -  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 normal limits.
  -  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.
  Exclusion Criteria:
  -  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 4 weeks.
  -  Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
  -  Active residual toxicity from prior therapies.
  -  Secondary malignancy.
  -  Brain metastases.
  -  Active autoimmune disease that has required systemic treatment within the last 2 years.
  -  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.
  -  Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia.
  -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  -  Uncontrolled symptomatic ascites or pleural effusions within 6 months.

Relevance to patient case: not relevant