Clinical trial NCT02798978: A Phase I, 2-part (Part 1 Being a Single Dose Escalation and Part 2, a Parallel Group) Study of Toll-like Receptor (TLR4) Agonist (GSK1795091) in Healthy Subjects
Official title: A 2-part Randomized, Double-blind (Sponsor-unblinded), Placebo-controlled, Ascending Dose and Parallel Group Study of TLR4 Agonist (GSK1795091) Administered to Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Neoplasms
Keywords: pharmacokinetics
TLR4 agonist
cancer
tolerability
GSK1795091
pharmacodynamics
safety
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-06-14
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is an ascending dose first-time-in-human study to determine the safety, tolerability, pharmacodynamic (PD), and pharmacokinetics (PK) profile of GSK1795091 in healthy subjects. The results will support the design of future clinical trials of GSK1795091 administered to subjects with advanced malignancies in combination with immune system modulators.

Part 1 will be a randomized, double-blind (sponsor-unblinded), placebo-controlled, single center, single dose escalation, sequential group evaluation of intravenously administered GSK1795091 to evaluate the safety and tolerability in healthy subjects. Part 2 will be an open-label, parallel group evaluation of 2 doses of GSK1795091 administered, either 1 week apart (Part 2, Cohort 1) or 2 weeks apart (Part 2, Cohort 2). In Part 2, on Day 1, subjects will receive intravenous GSK1795091 at a dose determined by results from Part 1. The total duration of this study is approximately 10 weeks from screening to the last study visit.


Eligibility criteria: Inclusion Criteria:

* Between 18 and 50 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and 12-lead ECG. (A subject with a clinically insignificant abnormality or laboratory parameter(s) may be included only if the Investigator documents that the finding is unlikely to represent a safety risk and will not interfere with the study procedures.)
* Body weight 55-95 kilogram (kg) and body mass index within the range 19-30 kg/meter (m)\^2 (inclusive).
* Male or Female of non-childbearing potential:

Males: Male subjects with female partners of child bearing potential must comply with the pre specified contraception requirements.

Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotropin test), not lactating, and is either of non-reproductive potential or reproductive potential. If of reproductive potential, then the subject should agree to follow one of the options listed per GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose and until 30 days after the last dose of study medication The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception

* Capable of giving signed informed consent

Exclusion Criteria:

* History of any significant medical condition (e.g. cardiac, pulmonary, metabolic, renal, gastrointestinal, rheumatological, etc.)
* History of frequent (\>1 per week) headache or myalgia, asthma, syncope.
* History of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome).
* Alanine aminotransferase (ALT) and bilirubin \>1.1×upper limit of normal (ULN; isolated bilirubin \>1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Vital signs:

Systolic blood pressure (SBP) \<90 and \>140 milliliter of mercury (mmHg); diastolic BP \<50 and \>90 mmHg; heart rate (HR) \<50 and \>90 beats per minute (bpm); temperature \>37.5 degree Celsius

* Clinically significant ECG abnormality and/or HR \< 50 and \>90 bpm; PR interval \>220 milliseconds (msec); QRS duration \>120 msec; and QTcF \> 450 msec
* Anticipated requirement for any prescription medication during the study
* History of regular alcohol consumption within 6 months of the study averaging a weekly intake of \>14 drinks for males or \>7 drinks for females or inability to abstain from alcohol from 1 day prior to the inpatient period of the study until discharge (one drink is equivalent to 8 grams of alcohol: 200 milliliter \[mL\] of beer, 100 mL of wine or 1 measure (25 mL) of spirits)
* Urinary cotinine levels indicative of smoking or history or regular use of tobacco or nicotine-containing products within 2 months prior to screening or inability to abstain from smoking during the study
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
* Presence of hepatitis B surface antigen, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid polymerase chain reaction test is obtained.
* A positive pre-study drug/alcohol screen.
* A positive test for human immunodeficiency antivirus antibody.
* Donation of blood or blood products in excess of 500 mL within a 56-day period.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first visit (Day -2) in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new chemical entities within 12 months prior to the first visit (Day -2).
* Exposure to GSK1795091 in a previous cohort of this study.
* Subject is unable to refrain from taking non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the investigator and sponsor, the medication will not interfere with the study.
* Subject is able to understand and communicate in German/or native language of the site. Subject, or close relative of the subject, is the investigator or a sub-investigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site
* Vulnerable subjects (eg subjects kept in detention)

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 32
measure: Change From Baseline in Body Temperature Part 1
timeFrame: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
measure: Change From Baseline in Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP) Part 1
timeFrame: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
measure: Change From Baseline in Pulse Rate Part 1
timeFrame: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
measure: Change From Baseline in Respiratory Rate Part 1
timeFrame: Baseline, Day 1 (1, 2, 4, 6, 8, 12, 16 hours), Day 2, Day 3, Day 4, Day 5, and Day 7.
measure: Number of Participants With Hematology Parameters Outside Reference Range Part 1
timeFrame: Up to Day 7
measure: Number of Participants With Clinical Chemistry Parameters Outside Reference Range
timeFrame: Up to Day 7
measure: Casts, Round Epithelial Cells (REC), Squamous Epithelial Cells (SEC), Urine Erythrocytes and Urine Leukocytes at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Ketones and Urine Glucose at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Occult Blood at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Urine Protein at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Specific Gravity at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Urine Potential of Hydrogen (pH) at Indicated Time Points
timeFrame: Pre-dose Day -1 and Day 1, Day 2, Day 4 and Day 7
measure: Number of Participants With Abnormal Electrocardiograms (ECG) Findings Worst Case Post-Baseline
timeFrame: Up to Day 32
Secondary outcomes:
measure: Maximum Observed Drug Concentration (Cmax) of GSK1795091 for Part 1
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Time of Occurrence of Cmax (Tmax) and Terminal Half Life (t1/2) of GSK1795091 for Part 1
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Partial Area Under the Concentration-time Curve to Time t (AUC[0-t]), Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK1795091 for Part 1
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Clearance (CL) of GSK1795091 for Part 1
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Volume of Distribution of GSK1795091 for Part 1
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Percentage Fold Change of Concentration of Interleukin 6 (IL-6) From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of Tumor Necrosis Factor (TNF)-Alpha From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of Interferon (IFN)-Gamma From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of Inducible Protein (IP)-10 From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of Monocyte Chemotactic Protein 1 (MCP-1) From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Colony Stimulating Factor 2 (GCSF) From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Interleukin 1 Receptor Antagonist (IL-1Ra) From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Interleukin 10 (IL-10) From Baseline for Part 1
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Change From Baseline in WBC Differential for Part 1
timeFrame: Baseline, 4, 24 and 144 hours
measure: Change From Baseline in CRP for Part 1
timeFrame: Baseline, Days 2, 4 and 7
measure: Maximum Observed Drug Concentration (Cmax) of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Time of Occurrence of Cmax (Tmax) and Terminal Half Life (t1/2) of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Partial Area Under the Concentration-time Curve to Time = t (AUC[0-t]), Area Under the Concentration-time Curve (AUC) From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Area Under the Concentration-time Curve (AUC) Time Curve for a Dosing Interval (AUC[0-tau]), AUC (0-last) of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Clearance (CL) of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Volume of Distribution of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Accumulation Ratio of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Time Invariance of GSK1795091 for Part 2
timeFrame: Pre-dose, 5 minutes, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 144 hours post-dose
measure: Percentage Fold Change of Concentration of Interleukin 6 (IL-6) From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of TNF-alpha From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of IFN-gamma From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of IP-10 From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of MCP-1 From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of GCSF From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of IL-1Ra From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Percentage Fold Change of Concentration of IL-10 From Baseline for Part 2
timeFrame: Baseline, 1, 2, 4, 8, 12, 16, 24, 48 and 144 hours
measure: Change From Baseline in WBC Differential for Part 2
timeFrame: Baseline, 2, 24 and 144 hours
measure: Number of Participants With Urinalysis Parameters Outside Reference Range for Part 2
timeFrame: Up to Day 7
measure: Number of Participants With Hematology Parameters Outside Reference Range in Part 2
timeFrame: Up to Day 7
measure: Number of Participants With Clinical Chemistry Parameters Outside Reference Range in Part 2
timeFrame: Up to Day 7
measure: Change From Baseline in CRP for Part 2
timeFrame: Baseline and Pre-dose, 1, 2, 4, 8, 12, 16, 24, and 48 hours post dose
measure: Change From Baseline in Body Temperature for Part 2
timeFrame: Baseline and up to Day 7
measure: Change From Baseline in SBP and DBP for Part 2
timeFrame: Baseline and up to Day 7
measure: Change From Baseline in Respiratory Rate for Part 2
timeFrame: Baseline and up to Day 7
measure: Change From Baseline in Pulse Rate for Part 2
timeFrame: Baseline and up to Day 7
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hug BA, Matheny CJ, Burns O, Struemper H, Wang X, Washburn ML. Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study. Clin Ther. 2020 Aug;42(8):1519-1534.e33. doi: 10.1016/j.clinthera.2020.05.022. Epub 2020 Jul 30.