Phase 1
Completed N=16
Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2831781 After an Intravenous (IV) Dose in Healthy Japanese and Caucasian Subjects, and a Subcutaneous (SC) Dose in Healthy Caucasian Subjects
Healthy Volunteers
Source: ClinicalTrials.gov NCT03965533 ↗
Enrolled (actual)
16
Serious AEs
2.8%
Results posted
Nov 2020
Primary outcomePrimary: Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) — 2; 5; 0; 4 Participants
Summary
This is a double-blind, placebo-controlled, randomized, parallel group, two-part study where single IV doses of GSK2831781 will be administered to healthy Japanese and Caucasian subjects in part A and SC doses will be administered to healthy Caucasian subjects in part B. GSK2831781 is a humanized, antibody-dependent cell cytotoxicity (ADCC) enhanced depleting monoclonal antibody that is specific to the lymphocyte activation gene-3 (LAG3) protein. LAG3 is a transmembrane receptor, which is upregulated on T cells following activation. The objective of the study is to assess the safety, tolerability, PK, PD and immunogenicity post administration of GSK2831781 in healthy subjects. The duration of the study is approximately 147 days for each subject enrolled. Approximately 36 subjects will be enrolled in the study, 16 subjects in Part A and 20 subjects in Part B.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) |
2; 5; 0; 4; 0; 0 | — |
| PRIMARY Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs) |
4; 6; 4; 0; 1; 0 | — |
| PRIMARY Part A: Number of Participants With Vital Signs of Potential Clinical Importance |
0; 1; 0; 0 | — |
| PRIMARY Part B: Number of Participants With Vital Signs of Potential Clinical Importance |
1; 0; 1 | — |
| PRIMARY Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance |
0; 1; 0; 2 | — |
| PRIMARY Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance |
0; 0; 1 | — |
| PRIMARY Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance |
0; 0; 0; 1 | — |
| PRIMARY Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance |
0; 0; 1 | — |
| PRIMARY Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI) |
2; 0; 0; 1 | — |
| PRIMARY Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance |
1; 0; 0 | — |
| PRIMARY Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings |
1; 0; 0; 0; 0; 0 | — |
| PRIMARY Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings |
0; 1; 0; 0; 0; 0 | — |
| PRIMARY Part A: Number of Participants With Injection Site Reaction |
0; 0; 0; 2 | — |
| PRIMARY Part B: Number of Participants With Injection Site Reaction |
0; 0; 0 | — |
| SECONDARY Part A: Area Under the Plasma Drug Concentration Versus Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0 to t]) of GSK2831781 Following IV Dose |
44261.755; 49650.933 | — |
| SECONDARY Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose |
137.61; 166.20 | — |
| SECONDARY Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose |
1.980; 1.990 | — |
| SECONDARY Part B: AUC(0 to t) of GSK2831781 Following SC Dose |
6633.227; 24269.036 | — |
| SECONDARY Part B: Cmax of GSK2831781 Following SC Dose |
14.61; 41.13 | — |
| SECONDARY Part B: Tmax of GSK2831781 Following SC Dose |
95.750; 120.270 | — |
| SECONDARY Part A and Part B: Bioavailability (F) of GSK2831781 Following IV Dosing at 450 mg (Caucasian and Japanese Participants) or SC Dosing at 150 mg and 450 mg (Caucasian Participants) |
76.5 | — |
| SECONDARY Degradation Rate of LAG3 Positive T Cells (Kout) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and Part B) |
0.0256 | — |
| SECONDARY Baseline of LAG3 Positive T Cell Count (CELL0) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) |
1.15 | — |
| SECONDARY Concentration of Free GSK2831781 at Which Half Maximum Effect on Kout is Achieved (EC50) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) |
9509 | — |
| SECONDARY Maximum Effect of Change in Kout (Emax) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) |
2.35 | — |
| SECONDARY Hill Coefficient (GAM) Derived From Statistical Analysis of the Relationship Between LAG3 Positive T Cell Levels in Blood and GSK2831781 Concentrations in Plasma (Part A and B) |
0.0942 | — |
| SECONDARY Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result |
0; 0; 0; 0 | — |
| SECONDARY Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result |
0; 0; 0 | — |
Eligibility Criteria
Inclusion Criteria
- Subjects who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and 12-lead ECGs. A subject with a clinical abnormality or laboratory parameter(s) outside the reference range for the population being studied that is not specifically listed in the inclusion or exclusion criteria may be included if the Investigator (in consultation with the Medical Monitor if required) agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or interpretation.
- Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- Body weight >=40 kilogram (kg) and body mass index (BMI) =5 mm, or PPD testing is not undertaken, the subject is not eligible.
- Any planned major surgical procedure during the study.
- A history of malignant neoplasm within the last 10 years, except for fully treated nonmetastatic basal or squamous cell cancers of the skin (within 3 years) that shows no evidence of recurrence.
- Use of prescription or non-prescription drugs (including recreational drugs and herbal medications) within 7 days or 5 half-lives (whichever is longer) prior to dosing, unless in the opinion of the investigator, the medication will not interfere with the study or compromise subject safety. Paracetamol (acetaminophen) at doses of 2x upper limit of normal (ULN) and bilirubin >1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin 450 millisecond (msec), based on the mean of triplicate ECGs. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF; preferred method), or another method, machine or overread.
- History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units. One unit is equivalent to 8 grams (g) of alcohol: a halfpint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
- Unstable lifestyle factors, to the extent that in the opinion of the investigator they would interfere with the ability of a subject to complete the study.
Data sourced from ClinicalTrials.gov (NCT03965533). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.