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

NCT03965533 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 207823
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

Japanese, Caucasian, pharmacokinetics, pharmacodynamics, GSK2831781, lymphocyte activation gene-3

Outcome Measures

Primary Outcomes (14)

• Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)

  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.

  Up to Day 112

• Part B: Number of Participants With Serious Adverse Events (SAEs) and Non-serious Adverse Events (Non-SAEs)

  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.

  Up to Day 112

• Part A: Number of Participants With Vital Signs of Potential Clinical Importance

  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.

  Up to Day 112

• Part B: Number of Participants With Vital Signs of Potential Clinical Importance

  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.

  Up to Day 112

• Part A: Number of Participants With Any Hematology Parameter of Potential Clinical Importance

  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.

  Up to Day 112

• Part B: Number of Participants With Any Hematology Parameter of Potential Clinical Importance

  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.

  Up to Day 112

• Part A: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance

  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.

  Up to Day 112

• Part B: Number of Participants With Any Clinical Chemistry Parameter of Potential Clinical Importance

  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.

  Up to Day 112

• Part A: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance (PCI)

  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.

  Up to Day 112

• Part B: Number of Participants With Any Urinalysis Parameter of Potential Clinical Importance

  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.

  Up to Day 112

• Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings

  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.

  Up to Day 112

• Part B: Number of Participants With Abnormal Electrocardiogram (ECG) Findings

  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.

  Up to Day 112

• Part A: Number of Participants With Injection Site Reaction

  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.

  Up to 24 hours (Day 1)

• Part B: Number of Participants With Injection Site Reaction

  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.

  Up to Day 8

Secondary Outcomes (14)

• 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

• 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

Study Arms (7)

Part A: Placebo IV- Caucasian Participants

PLACEBO COMPARATOR

Caucasian male participants were administered a single IV infusion of 0.9% weight by volume (w/v) saline placebo.

Drug: Placebo

Part A: GSK2831781 450 mg IV- Caucasian Participants

EXPERIMENTAL

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.

Drug: GSK2831781

Part A: Placebo IV- Japanese Participants

PLACEBO COMPARATOR

Japanese male participants were administered a single IV infusion of 0.9% w/v saline placebo.

Drug: Placebo

Part A: GSK2831781 450 mg IV- Japanese Participants

EXPERIMENTAL

Japanese male participants were administered a single IV infusion of GSK2831781 at a dose of 450 mg, diluted in 0.9% w/v saline.

Drug: GSK2831781

Part B: Placebo SC

PLACEBO COMPARATOR

Caucasian male participants were administered three SC injections of 0.9% w/v saline placebo.

Drug: Placebo

Part B: GSK2831781 150 mg SC

EXPERIMENTAL

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.

Drug: GSK2831781

Part B: GSK2831781 450 mg SC

EXPERIMENTAL

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.

Drug: GSK2831781

Interventions

GSK2831781 DRUG

GSK2831781 will be available as Dose-1 and Dose-2 as IV infusion or SC injection. Subjects will receive GSK2831781 Dose-1 IV diluted in 0.9% saline or GSK2831781 SC as multiples of Dose-2 SC.

Part A: GSK2831781 450 mg IV- Caucasian Participants; Part A: GSK2831781 450 mg IV- Japanese Participants; Part B: GSK2831781 150 mg SC; Part B: GSK2831781 450 mg SC

Placebo DRUG

Placebo will be 0.9% saline solution which will be administered in subjects as IV infusion or SC injection.

Part A: Placebo IV- Caucasian Participants; Part A: Placebo IV- Japanese Participants; Part B: Placebo SC

Eligibility Criteria

• Age: 18 Years - 65 Years
• Gender Eligibility Details: Male subjects will be included in the study
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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).
• Male.
• 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).
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: May 29, 2019
• Study Start: June 10, 2019
• Primary Completion: December 10, 2019
• Study Completion: December 10, 2019
• Last Updated: November 18, 2020
• Results First Posted: November 18, 2020

Record last verified: 2020-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (1)