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

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Cancer

Treatments: Drug: Afuresertib HPMC capsule - Fed State; Drug: Afuresertib ECT - Fed State; Drug: Afuresertib HPMC capsule - Fasted State; Drug: Afuresertib GC - Fasted State; Drug: Afuresertib ECT - Fasted State; Drug: Afuresertib GC - Fed State

Study type: Interventional

Funder types: Industry

Identifiers

NCT01827644

117313

Details and patient eligibility

About

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.

Enrollment: 36 patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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36 participants in 6 patient groups

Sequence 1

Experimental group

Description:

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

Treatment:

Drug: Afuresertib HPMC capsule - Fed State

Drug: Afuresertib HPMC capsule - Fasted State

Drug: Afuresertib GC - Fasted State

Drug: Afuresertib ECT - Fasted State

Sequence 2

Experimental group

Description:

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.

Treatment:

Drug: Afuresertib GC - Fed State

Drug: Afuresertib GC - Fasted State

Drug: Afuresertib ECT - Fed State

Drug: Afuresertib ECT - Fasted State

Sequence 3

Experimental group

Description:

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.

Treatment:

Drug: Afuresertib GC - Fed State

Drug: Afuresertib HPMC capsule - Fasted State

Drug: Afuresertib GC - Fasted State

Drug: Afuresertib ECT - Fed State

Sequence 4

Experimental group

Description:

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

Treatment:

Drug: Afuresertib HPMC capsule - Fed State

Drug: Afuresertib GC - Fed State

Drug: Afuresertib HPMC capsule - Fasted State

Drug: Afuresertib ECT - Fasted State

Sequence 5

Experimental group

Description:

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

Treatment:

Drug: Afuresertib HPMC capsule - Fed State

Drug: Afuresertib GC - Fed State

Drug: Afuresertib HPMC capsule - Fasted State

Drug: Afuresertib ECT - Fed State

Sequence 6

Experimental group

Description:

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

Treatment:

Drug: Afuresertib HPMC capsule - Fed State

Drug: Afuresertib GC - Fasted State

Drug: Afuresertib ECT - Fed State

Drug: Afuresertib ECT - Fasted State