Clinical trial NCT03154086: A Phase 1, First Time in Human (FTIH) Study to Evaluate GSK3352589, a REarranged During Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Volunteers
Official title: A Phase I, First Time in Human, Two Part, Randomized, Placebo-Controlled, Double-Blind (Sponsor Unblind), Single and Repeat Dose Escalating Study to Evaluate the Safety, Tolerability and Pharmacokinetics of GSK3352589, a REarranged During Transfection (RET) Growth Factor Receptor Tyrosine Kinase Inhibitor, in Normal Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Irritable Bowel Syndrome
Keywords: REarranged during Transfection
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-05-15
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This FTIH study is designed to assess the safety, tolerability and pharmacokinetic (PK) of escalating single and repeat oral doses of GSK3352589 in normal healthy volunteers. This is a randomized, double-blind (sponsor unblinded), placebo controlled, dose escalation study that will have two parts; Part A and Part B.


Eligibility criteria: Inclusion Criteria:

* Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
* Healthy as determined by the investigator based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. - History of regular bowel habits
* Male or Female of non-childbearing potential.
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions.

Exclusion Criteria:

* ALT and bilirubin \>1.5 x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Previous Diagnosis of IBS
* Estimated Glomerular Filtration Rate \<60 millilter per minute per 1.73 square meter (mL/min/1.73m\^2)
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
* History of Gastroesophageal reflux disease (GERD), dyspepsia, Gastrointestinal (GI) bleeding, diverticulitis, diverticular stricture or other intestinal strictures, GI surgery that could affect motility
* Unwillingness or inability to follow the procedures outlined in the protocol

Primary outcomes:
measure: Part A: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs in Cohort 1
timeFrame: Up to 64 days in Cohort 1
measure: Part A: Number of Participants With SAEs and Non-SAEs in Cohort 2
timeFrame: Up to 30 days in Cohort 2
measure: Part A: Number of Participants With SAEs and Non-SAEs in Cohort 3
timeFrame: Up to 30 days in Cohort 3
measure: Part B: Number of Participants With SAEs and Non-SAEs
timeFrame: Up to 25 days
measure: Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 1
timeFrame: Up to 64 days in Cohort 1
measure: Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 2
timeFrame: Up to 30 days in Cohort 2
measure: Part A: Number of Participants With Abnormal Findings After Physical Examination in Cohort 3
timeFrame: Up to 30 days in Cohort 3
measure: Part B: Number of Participants With Abnormal Findings After Physical Examination
timeFrame: Up to 25 days
measure: Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings in Cohort 1 and Cohort 3
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2
measure: Part A: Number of Participants With Abnormal ECG Findings in Cohort 2
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2
measure: Part B: Number of Participants With Abnormal ECG Findings
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 7 (Pre-dose, 4 Hours Post-dose), Day 14 (Pre-dose, 4 Hours Post-dose), Follow-up (Day 25)
measure: Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in Cohort 1 and Cohort 3
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part A: Change From Baseline in SBP and DBP in Cohort 2
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part B: Change From Baseline in SBP and DBP
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)
measure: Part A: Change From Baseline in Pulse Rate in Cohort 1 and Cohort 3
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part A: Change From Baseline in Pulse Rate in Cohort 2
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part B: Change From Baseline in Pulse Rate
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)
measure: Part A: Change From Baseline in Body Temperature in Cohort 1 and Cohort 3
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part A: Change From Baseline in Body Temperature in Cohort 2
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (1, 4, 12 Hours Post-dose), Day 2 and Day 3
measure: Part B: Change From Baseline in Body Temperature
timeFrame: Baseline (Pre-dose on Day 1), Day 1 (4 Hours Post-dose), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7 (Pre-dose, 4 Hours Post-dose), Day 8, Day 9, Day 10, Day 11, Day 12, Day 13, Day 14 (Pre-dose, 4 Hours Post-dose), Day 15, Follow-up (Day 25)
measure: Part A: Number of Participants With Different Stool Types Assessed Using Bristol Stool Form Scale (BSFS) in Cohort 1
timeFrame: Up to 64 days in Cohort 1
measure: Part A: Number of Participants With Different Stool Types Assessed Using BSFS in Cohort 2
timeFrame: Up to 30 days in Cohort 2
measure: Part A: Number of Participants With Different Stool Types Assessed Using BSFS in Cohort 3
timeFrame: Up to 30 days in Cohort 3
measure: Part B: Average BSFS at Indicated Time Points
timeFrame: Day -1, Days 1-3, Days 4-7, Days 1-7, Days 8-14
measure: Part A: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes in Cohort 1 and Cohort 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, Leukocytes
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Erythrocytes in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Erythrocytes in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Erythrocytes
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Hemoglobin in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Hemoglobin in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Hemoglobin
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Erythrocyte Mean Corpuscular Volume (MCV) in Cohort 1 and Cohort 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Erythrocyte MCV in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Erythrocyte MCV
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Erythorocyte Mean Corpuscular Hemoglobin (MCH) in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Erythrocyte MCH in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Erythrocyte MCH
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Hematocrit in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Hematocrit in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Hematocrit
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Alanine Aminotransferase (ALT),Aspartate Aminotransferase (AST), Alkaline Phosphatase (Alk Phos) in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in ALT, AST and Alk Phos in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in ALT, AST and Alk Phos
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Bilirubin, Creatinine, Direct Bilirubin
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Calcium, Glucose, Potassium, Sodium, Urea
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Change From Baseline in Albumin and Total Protein in Cohort 1 and 3
timeFrame: Baseline (Day -1) and Day 3
measure: Part A: Change From Baseline in Albumin and Total Protein in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Change From Baseline in Albumin, Total Protein
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Number of Participants With Abnormal Findings for Urine Parameters in Cohort 1 and Cohort 3
timeFrame: Baseline (Day-1) and Day 3
measure: Part A: Number of Participants With Abnormal Findings for Urine Parameters in Cohort 2
timeFrame: Baseline (Day -1) and Day 3
measure: Part B: Number of Participants With Abnormal Findings for Urine Parameters
timeFrame: Baseline (Day -2), Day 7, Day 15 and Follow-up (Day 25)
measure: Part A: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Non-zero Concentration (AUC [0-t]) Following Single Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: Maximum Observed Plasma Concentration (Cmax) Following Single Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: Time to Reach Cmax (Tmax) Following Single Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: Terminal Elimination Half-life (t1/2) Following Single Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: Cmax Following Single Dose Administration of GSK3352589-Food Effect
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: AUC (0-t) Following Single Dose Administration of GSK3352589- Food Effect
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part A: AUC (0-infinity) Following Single Dose Administration of GSK3352589- Food Effect
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 12, 16, 24, 36, 48 Hours Post-dose
measure: Part B: AUC (0-t) Following Repeat Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14
measure: Part B: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to 24 Hours Post-dose (AUC [0-24]) Following Repeat Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14
measure: Part B: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14
measure: Part B: Cmax Following Repeat Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14
measure: Part B: Tmax Following Repeat Dose Administration of GSK3352589
timeFrame: Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 1; Pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 10, 11, 12, 14, 16, 24 Hours Post-dose on Day 14
Secondary outcomes:
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: GSK Investigational Site
state: South Australia
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Reedy BA, O'Connor-Semmes R, Hacquoil K, Gorycki P, Verticelli A, Molga A. First-in-Human Study for a Selective Rearranged During Transfection Tyrosine Kinase Inhibitor, GSK3352589, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers. Clin Pharmacol Drug Dev. 2021 Apr;10(4):334-345. doi: 10.1002/cpdd.911. Epub 2021 Feb 19.