A Randomised, Double-blind, Placebo-controlled Phase I Study of the Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of a Single Intravenous Dose of GSK2831781 in Healthy Japanese and Caucasian Participants, and a Single Subcutaneous Dose of GSK2831781 in Healthy Caucasian Participants
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Healthy Volunteers
- Sponsor
- GlaxoSmithKline
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief 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.
Investigators
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) \<=30 kilogram per meter square (kg/m\^2).
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Japanese ancestry, defined as having been born in Japan, being descendants of four ethnic Japanese grandparents and two ethnic Japanese parents, holding a Japanese passport or identity papers, and being able to speak Japanese. Subjects should have lived outside Japan for less than 10 years at the time of screening.
- •Caucasian ancestry, defined as Caucasian descent as evidenced by appearance and verbal confirmation of familial heritage (a subject has 2 Caucasian parents and 4 Caucasian grandparents).
Exclusion Criteria
- •History or presence of a disease that in the opinion of the investigator constitutes a risk when taking the study intervention or interfering with study assessment or interpretation of the data.
- •A medical history of severe allergic reaction, angioedema, anaphylaxis, clinically significant drug hypersensitivity reaction, or autoimmune or immunodeficiency disorder.
- •An active infection or a history of serious infections as follows:
- •Use of antimicrobials (antibacterials, antivirals, antifungals or antiparasitic agents) for an infection within 30 days before first dose. Topical treatments may be allowed at the Medical Monitor's discretion.
- •A history of opportunistic infections.
- •Recurrent or chronic infection, or other active infection, that in the opinion of the Investigator might cause this study to be detrimental to the subject.
- •Symptomatic herpes zoster within 3 months prior to screening.
- •History of tuberculosis (TB) (active or latent) irrespective of treatment status.
- •A positive diagnostic TB test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the subject may have the test repeated once and if their second test is negative they will be eligible. In the event a second test is also indeterminate, the investigator has the option to undertake purified protein derivative (PPD) testing. If the PPD reaction is \<5 millimeter (mm) at 48 to 72 hours, then the subject is eligible. If the reaction is \>=5 mm, or PPD testing is not undertaken, the subject is not eligible.
- •Any planned major surgical procedure during the study.
Arms & Interventions
Part A: Placebo IV- Caucasian Participants
Caucasian male participants were administered a single IV infusion of 0.9% weight by volume (w/v) saline placebo.
Intervention: Placebo
Part A: GSK2831781 450 mg IV- Caucasian Participants
Caucasian male participants were administered a single IV infusion of GSK2831781 at a dose of 450 milligram (mg), diluted in 0.9% w/v saline.
Intervention: GSK2831781
Part A: Placebo IV- Japanese Participants
Japanese male participants were administered a single IV infusion of 0.9% w/v saline placebo.
Intervention: Placebo
Part A: GSK2831781 450 mg IV- Japanese Participants
Japanese male participants were administered a single IV infusion of GSK2831781 at a dose of 450 mg, diluted in 0.9% w/v saline.
Intervention: GSK2831781
Part B: Placebo SC
Caucasian male participants were administered three SC injections of 0.9% w/v saline placebo.
Intervention: Placebo
Part B: GSK2831781 150 mg SC
Caucasian male participants were administered a single SC injection of a unit dose strength of 150 mg per milliliter (mL) of GSK2831781, diluted in 0.9% w/v saline. Participants also received 2 dummy injections of 0.9% w/v saline placebo SC to maintain the blinding.
Intervention: GSK2831781
Part B: GSK2831781 450 mg SC
Caucasian male participants were administered three SC injections of a unit dose strength of 150 mg per mL of GSK2831781 to achieve a dose of 450 mg.
Intervention: GSK2831781
Outcomes
Primary Outcomes
Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
Time Frame: Up to Day 112
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Number of participants who had SAEs and non-SAEs are presented.
Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)
Time Frame: Up to Day 112
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician. Number of participants who had SAEs and non-SAEs are presented.
Part A: Number of Participants With Vital Signs of Potential Clinical Importance
Time Frame: Up to Day 112
Vital signs were measured in a semi-supine position after five minutes of rest and included temperature, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate. The clinical concern range for the parameters were: SBP (low: \<85 millimeters of mercury \[mmHg\] and high: \>160 mmHg), DBP (low: \<45 mmHg and high: \>100 mmHg), heart rate (low: \<40 beats per minute \[bpm\] and high: \>110 bpm) and temperature (low: \<35 degrees celsius \[°C\] and high: \>=37.5 °C). Number of participants with any vital sign value of potential clinical importance is reported.
Part B: Number of Participants With Vital Signs of Potential Clinical Importance
Time Frame: Up to Day 112
Vital signs were measured in a semi-supine position after five minutes of rest and included temperature, SBP, DBP and heart rate. The clinical concern range for the parameters were: SBP (low: \<85 mmHg and high: \>160 mmHg), DBP (low: \<45 mmHg and high: \>100 mmHg), heart rate (low: \<40 bpm and high: \>110 bpm) and temperature (low: \<35 °C and high: \>=37.5 °C). Number of participants with any vital sign value of potential clinical importance is reported.
Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance
Time Frame: Up to Day 112
Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from Baseline \<0.075 proportion of red cells in blood); hemoglobin (high: \>180 grams per liter \[g/L\] and low: change from Baseline \<25 g/L), lymphocytes (low: \<0.8 Giga cells per liter \[Giga cells/L\]); neutrophil count (low: \<1.5 Giga cells/L); eosinophil count (high: \>1 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L) and white blood cells count (low: \<3 Giga cells/L and high: \>20 Giga cells/L). Number of participants with any hematology parameter value of potential clinical importance is reported.
Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance
Time Frame: Up to Day 112
Blood samples were collected for the assessment of hematology parameters. The clinical concern range for the parameters were: hematocrit (high: \>0.54 proportion of red blood cells in blood and low: change from Baseline \<0.075 proportion of red cells in blood); hemoglobin (high: \>180 g/L and low: change from Baseline \<25 g/L), lymphocytes (low: \<0.8 Giga cells/L); neutrophil count (low: \<1.5 Giga cells/L); eosinophil count (high: \>1 Giga cells/L); platelet count (low: \<100 Giga cells/L and high: \>550 Giga cells/L) and white blood cells count (low: \<3 Giga cells/L and high: \>20 Giga cells/L). Number of participants with any hematology parameter value of potential clinical importance is reported.
Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance
Time Frame: Up to Day 112
Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: alanine aminotransferase (high: \>=2 times upper limit of normal \[ULN\]); aspartate aminotransferase (high: \>=2 times ULN); alkaline phosphatase (high: \>=2 times ULN); total bilirubin (high: \>=1.5 times ULN); blood urea nitrogen (high: \>10.5 millimoles per liter \[mmol/L\]); calcium (low: \<2 mmol/L and high: \>2.75 mmol/L); creatinine (high: change from Baseline \>26 micromoles per liter); estimated glomerular filtration rate (low: \<60 milliliter per minute per 1.73 squared meter); glucose (low: \<3 mmol/L and high: \>9 mmol/L); potassium (low: \<3 mmol/L and high: \>5.5 mmol/L); sodium (low: \<130 mmol/L and high: \>150 mmol/L) and total protein (low: \<50 g/L and high: \>85 g/L). Number of participants with any clinical chemistry parameter value of potential clinical importance is reported.
Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Time Frame: Up to Day 112
Twelve-lead ECGs were recorded with the participants in a semi-supine position, after 5 minutes of rest using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT and QTc intervals. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Part A: Number of Participants With Injection Site Reaction
Time Frame: Up to 24 hours (Day 1)
Local tolerability as measured by injection site reaction example; bruise at the site of injection and/or itching, pain, blistering or skin damage. Number of participants with any injection site reaction are presented.
Part B: Number of Participants With Injection Site Reaction
Time Frame: Up to Day 8
Local tolerability as measured by injection site reaction example; bruise at the site of injection and/or itching, pain, blistering or skin damage. Number of participants with any injection site reaction are presented.
Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI)
Time Frame: Up to Day 112
Urine samples were analyzed for bilirubin (Bil.),glucose (Gl.),ketones (Keto),leukocytes (leuko),nitrite (Nit.),occult blood (OB) and protein (Pro.) by dipstick method. Urine red blood cells (RBC) and white blood cells (WBC) were assessed by microscopy. Urine potential of hydrogen (pH) and specific gravity (Sp.Gr.) were also analyzed. The dipstick results are read as Trace,1+,2+ indicating proportional concentrations. pH is measured on a numeric scale of 0 to 14 (pH 7: neutral, pH \<7: acidic and pH \>7: basic). Urine Sp. Gr. is a measure of the concentration of solutes in the urine and indicated as ratio of urine density to water density. The clinical concern range for these parameters were: Bil., Gl., Leuko, OB and Pro. (high: \>1+),Keto (high: \>2+),Nit. (high: positive),pH (low: \<4.6 and high: \>8),Sp.Gr. (low: \<1.001 and high: \>1.035),RBC (high: \>3 cells/high power field \[hpf\]) and WBC (high: \>5 cells/hpf). Number of participants with any urinalysis parameter value of PCI is reported.
Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance
Time Frame: Up to Day 112
Blood samples were collected for the assessment of clinical chemistry parameters. The clinical concern range for the parameters were: alanine aminotransferase (high: \>=2 times ULN); aspartate aminotransferase (high: \>=2 times ULN); alkaline phosphatase (high: \>=2 times ULN); total bilirubin (high: \>=1.5 times ULN); blood urea nitrogen (high: \>10.5 mmol/L\]); calcium (low: \<2 mmol/L and high: \>2.75 mmol/L); creatinine (high: change from Baseline \>26 micromoles per liter); estimated glomerular filtration rate (low: \<60 milliliter per minute per 1.73 squared meter); glucose (low: \<3 mmol/L and high: \>9 mmol/L); potassium (low: \<3 mmol/L and high: \>5.5 mmol/L); sodium (low: \<130 mmol/L and high: \>150 mmol/L) and total protein (low: \<50 g/L and high: \>85 g/L). Number of participants with any clinical chemistry parameter value of potential clinical importance is reported.
Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance
Time Frame: Up to Day 112
Urine samples were analyzed for Bil., Gl., Keto, leuko, Nit., OB and Pro. by dipstick method. Urine RBC and WBC were assessed by microscopy. Urine pH and Sp.Gr. were also analyzed. The dipstick results are read as Trace, 1+, 2+ indicating proportional concentrations. pH is measured on a numeric scale of 0 to 14 (pH 7: neutral, pH \<7: acidic and pH \>7: basic). Urine Sp. Gr. is a measure of the concentration of solutes in the urine and indicated as ratio of urine density to water density. The clinical concern range for these parameters were: Bil., Gl., Leuko, OB and Pro. (high: \>1+), Keto (high: \>2+), Nit. (high: positive), pH (low: \<4.6 and high: \>8), Sp.Gr. (low: \<1.001 and high: \>1.035), RBC (high: \>3 cells/hpf) and WBC (high: \>5 cells/hpf). Number of participants with any urinalysis parameter value of PCI is reported.
Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
Time Frame: Up to Day 112
Twelve-lead ECGs were recorded with the participants in a semi-supine position, after 5 minutes of rest using an ECG machine that automatically calculated heart rate and measured PR, QRS, QT and corrected QT (QTc) intervals. Number of participants with worst-case clinically significant and not clinically significant abnormal ECG findings have been presented. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Secondary Outcomes
- 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(Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112)
- Part A: Maximum Observed Plasma Concentration (Cmax) of GSK2831781 Following IV Dose(Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112)
- Part A: Time to Maximum Observed Plasma Concentration (Tmax) of GSK2831781 Following IV Dose(Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112)
- 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)(Up to Day 112)
- Part B: AUC(0 to t) of GSK2831781 Following SC Dose(Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112)
- Part B: Cmax of GSK2831781 Following SC Dose(Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112)
- Part B: Tmax of GSK2831781 Following SC Dose(Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112)
- 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)(Part A (IV): Day 1 (Pre-dose and 1, 2, 6, 12, 24 hours post-dose); Days 3, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 112; Part B (SC): Day 1 (Pre-dose); Days 2, 3, 4, 6, 8, 11, 15, 18, 22, 29, 43, 57, 71, 85 and 112)
- 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)(Up to Day 112)
- Part A: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result(Up to Day 112)
- Part B: Number of Participants With Confirmed Positive Post-Baseline Anti-drug Antibody Result(Up to Day 112)
- 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)(Up to Day 112)
- 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)(Up to Day 112)
- 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)(Up to Day 112)