Bioavailability and Food Effect of the Original Gelatin Formulation and Two New Formulations of Afuresertib in Normal Healthy Volunteers

Study Overview
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Brief Summary
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This will be a randomized, open-label, sequential, single dose, 4-period crossover study. This study is being conducted to measure the relative bioavailability of the original gelatin capsule (GC) formulation and two new formulations (hydroxypropyl-methylcellulose [HPMC] capsule and enteric coated tablet [ECT]) of afuresertib (AFU), in the fed and fasted state. The study will be composed of Screening, Treatment, and Follow-up Periods. Screening assessments to determine subject eligibility will be performed within 3 weeks prior to the first dose of study drug in the Treatment Period. Eligible subjects will be randomized to receive 4 of the 6 possible study treatments (A: AFU GC administered in a fasted state, B: AFU GC administered in a fed state, C: AFU HPMC capsule administered in a fasted state, D: AFU HPMC capsule administered in a fed state, E: AFU ECT administered in a fasted state, F: AFU ECT administered in a fed state) in 4 treatment periods (one per treatment period). Subjects will receive a single dose of one of the six study treatments (A, B, C, D, E, F) on Day 1 of each Dosing Period, according to one of the 6 treatment sequences (CEDA, EFAB, ABFC, BDCE, FCBD, DAEF). There will be a minimum of 10 Day washout period between the doses administered in each Treatment Period. A Follow-up visit will be conducted within 10-14 days after the last dose. A subject's total time involved in the study will be approximately 9 weeks. At least 36 subjects will be enrolled in the study, to ensure that at least 6 subjects will be randomized to receive each treatment sequence.

Official Title
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A Single Center, Randomized, Open-Label, Sequential, Single Dose, 4-Period Crossover Study to Evaluate the Bioavailability and Food Effect of a Gelatin Formulation and Two Prototype Formulations of Afuresertib, an AKT Inhibitor, in Normal Healthy Volunteers

Conditions
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Cancer

Intervention / Treatment
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* Drug: Afuresertib GC - Fasted State
* Drug: Afuresertib HPMC capsule - Fasted State
* Drug: Afuresertib ECT - Fasted State
* Drug: Afuresertib GC - Fed State
* Drug: Afuresertib HPMC capsule - Fed State
* Drug: Afuresertib ECT - Fed State


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. Male or female between 18 and 40 years of age inclusive, at the time of signing the informed consent Body weight >=50 kilograms (kg) and body mass index (BMI) <=32 kg/m^2 (square meter) 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 acceptable contraception methods. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5 x Upper Limit of Normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Based on single or averaged corrected QT interval (QTc) values of triplicate electrocardiograms (ECGs) obtained over a brief recording period: QTc <450 milliseconds (msec) or QTc <480 msec in subjects with Bundle Branch Block 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 (GERD), dyspepsia, 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 8 grams (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. History of sensitivity to heparin or heparin-induced thrombocytopenia 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 Use of prescription or non-prescription medications, vitamins, and dietary or herbal supplements (including St John's Wort) within 7 days (or 14 days if the drug/supplement is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study drug until completion of the Follow-up Period, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study Unable to abstain from smoking tobacco or the use of nicotine-containing products while admitted to the clinic Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of Study Drug on Day 1 of Dosing Period 1, until completion of the Follow-up Period A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening History of heavy 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 Immunodeficiency 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1<br>Subjects will receive single doses of AFU HPMC capsule administered in a fasted state, AFU ECT administered in a fasted state, AFU HPMC capsule administered in a fed state and AFU GC administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period | Drug: Afuresertib GC - Fasted State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state<br>Drug: Afuresertib HPMC capsule - Fasted State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state<br>Drug: Afuresertib ECT - Fasted State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state<br>Drug: Afuresertib HPMC capsule - Fed State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state<br>|
| Experimental: Sequence 2<br>Subjects will receive single doses of AFU ECT administered in a fasted state, AFU ECT administered in a fed state, AFU GC administered in a fasted state and AFU GC administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period. | Drug: Afuresertib GC - Fasted State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state<br>Drug: Afuresertib ECT - Fasted State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state<br>Drug: Afuresertib GC - Fed State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state<br>Drug: Afuresertib ECT - Fed State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state<br>|
| Experimental: Sequence 3<br>Subjects will receive single doses of AFU GC administered in a fasted state, AFU GC administered in a fed state, AFU ECT administered in a fed state and AFU HPMC capsule administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period. | Drug: Afuresertib GC - Fasted State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state<br>Drug: Afuresertib HPMC capsule - Fasted State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state<br>Drug: Afuresertib GC - Fed State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state<br>Drug: Afuresertib ECT - Fed State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state<br>|
| Experimental: Sequence 4<br>Subjects will receive single doses of AFU GC administered in a fed state, AFU HPMC capsule administered in a fed state, AFU HPMC capsule administered in a fasted state and AFU ECT administered in a fasted state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period | Drug: Afuresertib HPMC capsule - Fasted State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state<br>Drug: Afuresertib ECT - Fasted State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state<br>Drug: Afuresertib GC - Fed State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state<br>Drug: Afuresertib HPMC capsule - Fed State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state<br>|
| Experimental: Sequence 5<br>Subjects will receive single doses of AFU ECT administered in a fed state, AFU HPMC capsule administered in a fasted state, AFU GC administered in a fed state and AFU HPMC capsule administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period | Drug: Afuresertib HPMC capsule - Fasted State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state<br>Drug: Afuresertib GC - Fed State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state<br>Drug: Afuresertib HPMC capsule - Fed State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state<br>Drug: Afuresertib ECT - Fed State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state<br>|
| Experimental: Sequence 6<br>Subjects will receive single doses of AFU HPMC capsule administered in a fed state, AFU GC administered in a fasted state, AFU ECT administered in a fasted state and AFU ECT administered in a fed state (sequentially), on Day 1 of Dosing Period 1, 2, 3 and 4 (one treatment per period) respectively, with a minimum 10 Day washout between the doses in each Dosing Period | Drug: Afuresertib GC - Fasted State<br>* White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state<br>Drug: Afuresertib ECT - Fasted State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fasted state<br>Drug: Afuresertib HPMC capsule - Fed State<br>* White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state<br>Drug: Afuresertib ECT - Fed State<br>* White to off white, round, biconvex coated tablet containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib ECT administered in fed state<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of plasma pharmacokinetics (PK) parameters of afuresertib, following administration with and without food | Relative bioavailability of afuresertib after single dose of a GC, HPMC capsule and ECT, with and without high fat/calorie meal, will be determined by the following PK parameters: Area under the plasma concentration time curve- from time zero (pre-dose) to infinite time [AUC(0-inf)] and from time zero (pre-dose) to last time of quantifiable concentration [AUC(0-t)], maximum observed plasma concentration (Cmax), time to Cmax (tmax), observed plasma concentration at 24 hours (C24), and minimal observed plasma concentration (Ct) | PK samples will be collected at Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours post-dose in each dosing period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of afuresertib as assessed by 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 | 
| Safety and tolerability of afuresertib as assessed by clinical laboratory tests | Hematology, clinical chemistry and urinalysis parameters will be measured | Up to 9 weeks | 
| Safety and tolerability of afuresertib as assessed by concomitant medications review |  | Up to 9 weeks | 
| Safety and tolerability of afuresertib as assessed by electrocardiograms (ECG) measurements | Triplicate 12-lead ECGs will be collected at Screening; on Day 1 and Day 3 of each Dosing Period; and at Follow-up | Up to 9 weeks | 
| Safety and tolerability of afuresertib as assessed by vital signs measurement | Vital sign measurements will include systolic and diastolic blood pressure and pulse rate | Up to 9 weeks | 
| Change in phosphoAKT (pAKT) levels in peripheral blood samples following administration of a gelatin capsule, HPMC capsule and ECT | The potential relationship between plasma PK and pharmacodynamic biomarker changes (pAKT) of each formulation will be evaluated | Pre-dose and 2, 12, and 24 hours post-dose in each dosing period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AKT inhibitor, formulation, food effect, bioavailability, GSK2110183