Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib

A Single Center, Randomized, Open-Label, Sequential, Single Dose, 3-Period Crossover Study to Evaluate the Bioavailability and Food Effect of a Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib, an AKT Inhibitor, in Normal Healthy Volunteers

This study is being conducted to measure the relative bioavailability of the original gelatin capsule formulation and a new formulation, immediate release (IR) tablet of Afuresertib (GSK2110183). The study will be composed of Screening, Treatment, and Follow-up Periods. A subject's total time involved in the study will be approximately 9 weeks. The study will enroll approximately 18 healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Cancer
• Intervention / Treatment: Drug: GSK2110183 Gelatin Capsule; Drug: GSK2110183 IR Tablet

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provided signed written informed consent
• Healthy Male or female between 18 and 40 years of age inclusive, at the time the informed consent is obtained.
• Body weight >=50 kilograms (kg) and body mass index (BMI) of >=18 and <= 32 kg/meter square (m^2).
• A female subject is eligible to participate if she is of (A) Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea (B) Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at Screening and prior to dosing, AND: agrees to use one of the acceptable contraception methods
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods.
• Alanine aminotransferase, alkaline phosphatase and bilirubin <=1.5xupper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• Based on single or averaged QT interval corrected (QTc) values of triplicate ECGs obtained over a brief recording period: QTcB <450 millisecond (msec); or QTcB <480 msec in subjects with Bundle Branch Block.
• Able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.

Exclusion Criteria:

• 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, dyspepsia, peptic ulcer disease, gastrointestinal (GI) bleeding, GI surgery that could affect motility.
• History of atrial arrhythmias
• History of regular alcohol consumption within 6 months of the study defined as:

An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 10 grams (g) of alcohol: 270 mL of full strength beer (4.8%), 375 mL of mid strength beer (3.5%), 470 mL of light beer (2.7%), 250 mL pre-mix full strength spirit (5%), 100mL of wine (13.5%) and 30 mL of spirit (40%).

• 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 GSK Medical Monitor, contraindicates their participation
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening.
• Smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
• A positive drug/alcohol screen at Screening or upon check-in to the clinic on Day -1 of each Dosing Period.
• A positive test for human immuno virus (HIV) antibody.
• Pregnant females as determined by positive serum hCG test at Screening or prior to dosing.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Lactating females.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day 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 dosing day.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Any prohibited medications or recent consumption of citrus products.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): ABC	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration
Experimental: Sequence 2; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): ACB	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration
Experimental: Sequence 3; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): BAC	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration
Experimental: Sequence 4; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): BCA	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration
Experimental: Sequence 5; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): CAB	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration
Experimental: Sequence 6; Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): CBA	Drug: GSK2110183 Gelatin Capsule; White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration; Drug: GSK2110183 IR Tablet; White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of pharmacokinetic (PK) parameters to determine relative bioavailability of afuresertib after administering it as a single dose in an original gelatin capsule in the fasted state and in a newly formulated IR tablet in the fed and fasted state.	PK parameters include: area under the plasma concentration-time curve from time zero to infinity (AUC [0-infinity]), area under the plasma concentration time curve from time zero to last time of quantifiable concentration (AUC [0-t]), maximum observed plasma concentration (Cmax), and time to Cmax (tmax).	PK Samples will be collected Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 120, and 168 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with adverse events (AEs).	AEs will be collected from the start of Study Treatment and until the Follow-up contact.	Up to 9 weeks
Clinical laboratory parameter assessment as a measure of safety and tolerability	Laboratory parameters include: hematology, clinical chemistry and urinalysis.	Up to 9 weeks
Concomitant medications review as a measure of safety and tolerability		Up to 9 weeks
Electrocardiogram (ECGs) measurement as a measure of safety and tolerability	Triplicate 12-lead ECGs will be collected at Screening; in each Dosing Period on Day 1 and Day 3 of Dosing Period; and at Follow-up.	Up to 9 weeks
Vital sign measurement as a measure of safety and tolerability	Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.	Up to 9 weeks
Composite of PK parameter following single dose administration of IR tablet in fasted state	PK parameters include: AUC (0 - infinity), AUC (0 - t), Cmax, and tmax.	PK Samples will be collected Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 120, and 168 hours post-dose

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2014
• Primary Completion (Actual): April 4, 2014
• Study Completion (Actual): April 4, 2014

Study Registration Dates

• First Submitted: January 16, 2014
• First Submitted That Met QC Criteria: January 16, 2014
• First Posted (Estimate): January 20, 2014

Study Record Updates

• Last Update Posted (Actual): November 13, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: bioavailability; food effect; formulation; AKT inhibitor; GSK2110183; afuresertib
• Other Study ID Numbers: 201039