Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): ABC

Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): ACB

Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): BAC

Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): BCA

Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): CAB

Participants will receive treatment in following sequence in each of the three study periods (one treatment per period): CBA

White opaque hard gelatin capsule with a unit dose strength of 25 milligrams (mg) for oral administration

GSK2110183 Gelatin Capsule

White round biconvex film coated IR tablet with a unit dose strength of 25 mg for oral administration

GSK2110183 IR Tablet

GSK Clinical Trials

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.

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

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).

AEs will be collected from the start of Study Treatment and until the Follow-up contact.

Laboratory parameters include: hematology, clinical chemistry and urinalysis.

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.

Vital sign measurements will include systolic and diastolic blood pressure and pulse rate.

PK parameters include: AUC (0 - infinity), AUC (0 - t), Cmax, and tmax.

GlaxoSmithKline

Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hematologic Neoplasms

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Dexamethasone

Bortezomib

Dexamethasone acetate

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

GSK2110183 is administered in combination with bortezomib and dexamethasone until MTD is met.

Once the MTD(s) has been determined, up to 9 subjects of the total enrolled in Part 2 will be entered in the Pharmacokinetic/Pharmacodynamic Cohort. Subjects will be enrolled in this cohort to explore whether exposure to GSK2110183 at dose identified in Part 1 is similar when GSK2110183 is administered alone or in combination with bortezomib and dexamethasone. The same relationship will be explored for bortezomib and dexamethasone when the two drugs are give alone or in combination with GSK2110183.

Enrolment into the safety/clinical activity cohort in Part 2 will begin prior to enrollment in the PK/PD cohort. Subjects with relapsed multiple myeloma who are either bortezomib sensitive or naive after failing one line of prior systemic therapy will be enrolled in the Safety/Clinical Activity cohort. "Bortezomib sensitive" is defined as having a response (PR or better) to the last bortezomib-containing therapy lasting at least 60 days beyond the end of therapy. A minimum of 15 subjects and a total of 40 subjects will be enrolled. This expansion cohort will further characterize the safety and clinical activity profile of GSK2110183 to inform the future development of this combination regimen.

The oral, once daily dose of GSK2110183 will be dependent on the cohort to which a subject is assigned. Subjects enrolled in Cohort 1 will receive 75 mg GSK2110183 once daily. Dose escalation in Schedule A and Schedule B will follow 25 mg increments in a 3+3 dose escalation procedure up to a maximum of 150mg daily or until MTD is reached, whichever comes first, for each schedule. GSK2110183 will continue at daily dosing until treatment discontinuation criteria is met.

GSK2110183

Bortezomib (1.0 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for cohort 1 for up to 8 cycles. Bortezomib (1.3 mg/m2) will be administered on days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Bortezomib (1.5 mg/m2) will be administered on days 1, 8, and 15 of each 21-day cycle for up to 8 cycles.

Dexamethasone will be given orally at a fixed dose of 20 mg only on days of bortezomib dosing in both Schedule A and Schedule B.

Novartis Pharmaceuticals

Phase Ib, open-label study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of GSK2110183 dosed in combination with bortezomib and dexamethasone in multiple myeloma (MM) subjects who have failed at least one line of systemic treatment. Part 1 will identify the maximum tolerated dose(s) (MTD) of the combination regimen. Schedule A - GSK2110183 administered once daily with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) given biweekly. Part 2 will further explore the safety, tolerability and clinical activity of the MTD(s) identified in Part 1, including a pharmacokinetic cohort.

This is a Phase Ib, open-label study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of GSK2110183 dosed in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM) subjects who have failed at least one line of systemic treatment. Part 1 will identify the maximum tolerated dose(s) (MTD) of the combination regimen.

Part 1, Schedule A will assess the safety and pharmacodynamics of GSK2110183 administered once daily with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) given biweekly. It is estimated that up to 35-45 evaluable subjects will be enrolled in Part 1. Part 2 will explore further the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of the MTD(s) identified in Part 1. A minimum of 15 and maximum of 40 subjects will enroll in Part 2 Safety/Clinical Activity Cohort for each Schedule explored. The Part 2 PK/PD cohort will enroll up to 18 subjects. This pharmacokinetic cohort will explore whether exposure to GSK2110183 at the MTD is similar when GSK2110183 is administered alone or in combination with bortezomib and dexamethasone. The same relationship will be explored for bortezomib and dexamethasone when the two drugs are given by themselves or in combination with GSK2110183. The identified MTD(s) and pharmacodynamic results in this study will inform the doses for future development of the regimen of GSK2110183 dosed in combination with bortezomib and dexamethasone in subjects with relapsed/refractory MM.

Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma

A Phase Ib Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the Oral AKT Inhibitor GSK2110183 Administered in Combination With Bortezomib and Dexamethasone in Subjects With Relapsed/Refractory Multiple Myeloma

Dose and schedule determined using adverse events and changes in safety assessments (laboratory parameters, vital signs and ECG parameters). Recommended Phase 2 Dose (RP2D) will be defined in Part 1. The specific number of subjects to be enrolled is dependent on the number of dose limiting toxicities (DLTs) reported; enrollment of up to 45 subjects in Part 1 is estimated. Subjects will continue on study from the date of randomization until the date of the first documented disease progression or when the subject meets one of the Treatment Discontinuation criteria, whichever comes first

Comparison of GSK2110183 area under the concentration versus time curve (AUC) values when administered alone versus when administered with bortezomib and dexamethasone. Comparison of bortezomib and dexamethasone AUC values when administered alone versus when administered with GSK2110183. Comparison of GSK2110183 maximum concentration (Cmax) values when administered alone versus when administered with bortezomib and dexamethasone. Comparison of bortezomib and dexamethasone Cmax values when administered alone versus when administered with GSK2110183.

The clinical response \[ i.e. changes in the M-protein, the serum free light chains (FLC) (kappa/lambda ratio ), the appearance of or the change in the size of plasmacytomas or lytic lesions in bone \] to GSK2110183, bortezomib and dexamethasone in subjects with relapsed/refractory multiple myeloma, as assessed by the International Myeloma Working Group Uniform Response Criteria

Explore the relationships between GSK2110183 exposure (AUC, Cmax concentration, minimum concentration), PD markers (e.g., changes in phosphorylation of markers of AKT (pAKT) pathway activation in bone marrow (BM) biopsy samples and clinical activity (M Protein levels, clinical response). In Part 2, Serial PK plasma samples collected on 2 days. Parts 1 and 2, samples for PD markers (BM biopsy and/or aspirate, plasma for circulating free DNA (cfDNA) or cytokine and angiogenic factors (CAFs)) collected. Parts 1 and 2, clinical activity (lab assessments, quantitative paraprotein) assessed.

Phosphorylation of markers of AKT pathway activation (i.e., pAKT and pPRAS40) in bone marrow biopsy samples. Exploratory analysis of potential predictive markers of response \[i.e., cytogenetics (CD45, CD138, CD38, CD19, CD56, CD20, CD117), FISH \[t(4;14), t(14;16), 17p13del, del(13q)\], Ki67, mutations in NRAS and KRAS\] and soluble cytokine levels (i.e., VEGF, IL-6, IFG1) in plasma. BM biopsy will assess markers of AKT activation. Plasma samples will assess circulating free DNA and CAFs. BM aspirate will assess potential predictive markers of response collected for FISH and cytogenetics.

Novartis

All patients received the GSK2110183 (afuresertib) treatment

Afuresertib is an oral, low nanomolar pan-AKT kinase inhibitor immediate release (IR) 50 mg or 75 mg tablets was to be taken orally with at least 200 mL of water, with or without food, in the morning.

GSK2110183 (afuresertib)

This multicenter, non-randomized, open-label, treatment continuation or 'rollover' study was designed to provide continued access to eligible subjects who had previously participated in a GSK2110183 study (parent study) sponsored by GlaxoSmithKline (GSK) or another research organization working on behalf of GSK. Eligible subjects had previously received clinical benefit from continued treatment and had to have ad an acceptable safety profile with GSK2110183. Subjects who had participated in a GSK2110183 combination study with an approved anti-cancer agent were also be eligible to enroll in this rollover study. Subjects who participated in combination studies with two investigational compounds (one being GSK2110183) were not eligible for this rollover study. Subjects were enrolled by cohort based on the duration and treatment received while in their parent study. Safety assessments (physical examinations, vital sign measurements, 12-lead electrocardiograms, echocardiograms or multiple-gated acquisition scans, clinical laboratory assessments and monitoring of adverse events) were evaluated during this study. Disease assessment were performed using local standard of care imaging practices and criteria appropriate for disease type and location.

Continuation Study of the Oral AKT Inhibitor GSK2110183

An Open Label Continuation Study of the Oral AKT Inhibitor GSK2110183 in Subjects With Solid Tumors and Hematologic Malignancies

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Adverse Events (AEs) includes Summary of adverse events, drug related AEs, Serious adverse events, adverse events leading to study treatment discontinuation and death.

All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of about 76 months.

All Patients

GSK2110183 (Afuresertib)

Age, Continuous

Sex: Female, Male

Asian - East Asian heritage

White - White/Caucasian/European heritage

Race/Ethnicity, Customized

The 'all treated subjects' population consisted of all subjects that received at least one dose of afuresertib in this rollover study.

Study Director

Number of Participants With at Least One Adverse Events (AEs)

Overall Study

Herbal and Botanical

Proteasome Inhibitors

Orange

The oral dose of GSK2110183 the subjects received will be dependent on when the subject is enrolled to the study. GSK2110183 will be provided in 25mg and 50mg capsules containing the hydrochloride salt form of the API, microcrystalline cellulose, magnesium stearate, and microcrystalline cellulose (optional). They are filled into hard gelatin capsules. The 25mg tablets are opaque, swedish orange, size 2 capsules with no external markings, filled with a white powder. The 50mg tablets are opaque, white, size 1 capsules with no external markings, filled with a white powder.

Bortezomib salvage therapy will be administered as a 3 to 5 second intravenous (IV) push at 1.3 mg/m2 on Days 1, 8, and 15 in each 21-day cycle until one of the Treatment Discontinuation Criteria is met.

On Cycle 0, Day -3, three subjects will be enrolled to receive a single oral dose of 125mg GSK2110183. After the 72 hour PK sampling is completed, the subjects will continue the 125mg GSK2110183 dose daily for 21 day cycles. If none of the 3 subjects experience one of the DLTs listed in the protocol during Cycle 1, the dose will be escalated to 150mg GSK2110183 for the subject enrolled to Cohort 2. Alternately, if 1 subject reports a DLT, then 3 more subjects will be enrolled at the same dose. If 2 of 6 subjects report a DLT, then the MTD has been exceeded. Subjects will remain on study until they meet one of the Treatment Discontinuation Criteria.

Part 1; Cohort 1

For Cohort 2, on Cycle 0, Day -3, three subjects will be enrolled to receive a single oral dose of 150mg GSK2110183. After the 72 hour PK sampling is completed, the subjects will continue the 150mg GSK2110183 dose daily for 21 day cycles. If none of the 3 subjects experience one of the DLTs listed in the protocol during Cycle 1, the MTD will be determined unless the PK and Pharmacodynamic data indicates another dose level should be evaluated. Alternately, if 1 subject reports a DLT, then 3 more subjects will be enrolled at the same dose. If 2 of 6 subjects report a DLT, then the MTD has been exceeded. Subjects will remain on study until they meet one of the Treatment Discontinuation Criteria.

Part 1; Cohort 2

Following the completion of PK sampling and the determination of a Recommended Phase 2 Dose (RP2D) of GSK2110183 in Cohorts 1 and 2, subjects will be enrolled into Part 2, Stage 1 of the study. Twenty subjects will be enrolled in Stage 1. If no subject responds, the study will be stopped; otherwise, the study will continue enrollment of Stage 2.

Part 2; Stage 1

Twenty subjects will be enrolled in Part 2, Stage 2. If 4 or fewer of the 40 subjects (Stages 1 and 2) respond, the study will not be deemed as a success for GSK2110183 monotherapy. However, those subjects meeting the criteria for progression (as defined by IMWC Panel 1) who also meet the additional eligibility criteria for salvage therapy may proceed to GSK2110183 + bortezomib salvage therapy. GSK2110183 + bortezomib salvage therapy will be continued until one of the Treatment Discontinuation Criteria is met

Part 2, Stage 2

This is a single arm, open-label, Phase Ib/II study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of the oral AKT inhibitor, GSK2110183, when administered to subjects with proteasome inhibitor refractory multiple myeloma (MM). During Part 1 of the study, GSK2110183 will be administered to subjects in sequential Pharmacokinetic (PK) Cohorts on a continuous daily dosing schedule in 21-day cycles until one of the Treatment Discontinuation Criteria is met. The PK Cohorts will characterize the PK of GSK2110183 in plasma and urine as well as determine the Recommended Phase 2 Dose (RP2D) of GSK2110183. The RP2D will be that dose that provides adequate PK exposure and biologic activity without exceeding the maximum tolerated dose (MTD) in MM subjects as defined in the current study. In Part 2 of the study, the RP2D will be further evaluated using a flexible 2-stage design with a stopping rule to allow for early termination based on lack of efficacy at the end of Stage 1. The first stage will accrue 20 subjects who will receive GSK2110183 at the RP2D. If a clinical response is observed in at least 1 subject in Stage 1, the study will proceed to Stage 2 and 20 additional subjects will be enrolled. GSK2110183 will be administered in Part 2 (Stage 1 and Stage 2) on a continuous daily dosing schedule in 21 day cycles until International Myeloma Working Group criteria for progression are met, at which point the subject will proceed to GSK 2110183 + bortezomib salvage therapy provided they meet the additional eligibility criteria for this phase of the study. GSK2110183 and bortezomib will be continued until one of the Treatment Discontinuation Criteria is met.

Exploratory PK/PD analyses may be performed to examine the potential relationships between GSK2110183 pharmacokinetics and pharmacodynamic biomarkers.

This is a single arm, open-label, Phase Ib/II study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of the oral AKT inhibitor GSK2110183 when administered to subjects with proteasome inhibitor refractory MM.

During Part 1 of the study, dose escalation will follow a 3 + 3 dose escalation procedure starting with an initial dosing regimen of 125 mg GSK2110183 with escalate to next dose level with an increase of GSK2110183 less than or equal to 50% if DLTs are below a certain level described in the protocol. Subjects will receive a single dose of GSK2110183 on Day -3 of Cycle 0, followed by PK sampling over the next 72 hours. Cycle 1 may commence at any time (but within 7 days) after collection of the 72 hour Cycle 0 PK sample. GSK2110183 will be administered to subjects in sequential PK Cohorts on a continuous daily dosing schedule in 21 day cycles until one of the Treatment Discontinuation Criteria is met. Sparse PK sampling will also be collected during the first 8 cycles. Urine PK samples will be collected prior to the first dose of GSK2110183 and as a 24-hour urine collection at steady-state. The PK Cohorts will characterize the pharmacokinetics of GSK2110183 in plasma and urine, as well as determine the RP2D of GSK2110183. The RP2D will be that dose that provides adequate PK exposure and biologic activity without exceeding the MTD in MM subjects as defined in the current study. GSK2110183 + bortezomib salvage therapy will not be given to subjects who progress on GSK2110183 monotherapy in the PK Cohorts. Following the completion of PK sampling in the PK Cohorts and the determination of a RP2D of GSK2110183, Part 2 of the study will then commence at the RP2D.

Part 2 of the study will further evaluate the R2PD using a flexible 2-stage design with a stopping rule to allow for early termination based on lack of efficacy at the end of Stage 1. GSK2110183 will be administered on a continuous daily dosing schedule in 21-day cycles until one of the Treatment Discontinuation Criteria is met. Twenty subjects will be enrolled in Stage 1, if no subject responds, the study will be stopped; otherwise, the study will continue to enroll an additional 20 subjects in Stage 2. At the end of Stage 2, if 4 or fewer of 40 subjects respond, the study will not be deemed as a success for the monotherapy. Those subjects meeting the criteria for progression during Part 2 \[as defined by the 2011 Report of the International Myeloma Workshop Consensus Panel 1\], who also meet the additional eligibility criteria for salvage therapy may proceed to GSK2110183 + bortezomib salvage therapy. GSK2110183 + bortezomib salvage therapy will be continued until one of the Treatment Discontinuation Criteria is met.

Exploratory PK/PD analyses may be performed in Part 1 and Part 2 to examine the potential relationships between GSK2110183 pharmacokinetics and pharmacodynamic biomarkers (e.g., pAKT, pPRAS40 in the bone marrow), markers for disease activity in serum (e.g., beta-2 microglobulin, C-reactive protein), or blood-based cytokines and angiogenesis factors (e.g., IL-6, VEGF).

A secondary objective of this study is to determine whether the addition of bortezomib to GSK2110183 has clinical activity in patients refractory to proteasome inhibitor therapy who progress on single-agent GSK2110183 therapy.

A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma

An Open-Label, Single Arm, Phase Ib/II Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma

Subjects with proteasome inhibitor refractory MM enrolled into Parts 1 and 2 will be evaluate for safety and tolerability of GSK2110183 by the assessment of adverse events and changes from baseline in safety assessments including laboratory parameters, vital signs, and electrocardiogram (ECG) parameters.

RP2D is defined as a dose that provides adequate pharmacokinetics exposure and biologic activity without exceeding the Maximum Tolerated Dose (MTD) in Multiple Myeloma (MM) subjects as defined in the current study. RP2D will be defined in Part 1 of the study. The specific number of subjects to be enrolled is dependent on the number of Dose Limiting Toxicities (DLTs) reported; however, enrollment of approximately 18 subjects is estimated. The RP2D chosedn in Part 1 will be the dosing regimen used in Part 2.

Subjects enrolled into Parts 1 and 2 will be assessed for overall response rate of GSK2110183 in subjects with proteasome inhibitor refractory Multiple Myeloma using the 2011 recommendations in the Report of the International Myeloma Workshop Consensus.

Subjects enrolled into Parts 1 and 2 will be assessed for PFS, OS, time to response, and duration of response using the 2011 Report of the International Myeloma Workshop Consensus Panel 1. PFS is measured from the date of first dose until the date of disease progression or death due to any cause. OS is defined as the time from the date of first dose until the date of death due to any cause. Duration of response will be defined as the time from the first documented evidence of partial, very good partial, complete, or stringent complete tumor response until date of disease progression or death

To characterize GSK2110183 pharmacokinetic parameters; area of concentration under the curve (AUC), Pre-dose (trough) concentration at the end of the dosing interval (Cτ), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax) will be evaluated in the plasma and urine samples. The main PK sampling will take place in Part 1 of the study and Part 2 will have only sparse PK sampling.

In Part 2 of the study, subjects whom bortezomib is added to GSK2110183 due to disease progression on GSK2110183 monotherapy overall response rate (ORR = stringent complete response + complete response + very good partial response + partial response rates), PFS, duration of response, and time-to-next-therapy will be evaluated.

Subjects enrolled into Parts 1 and 2 will have samples collected for analysis of the markers of AKT pathway activation (e.g., pAKT, pPRAS40) in bone marrow biopsy and/or aspirate samples, potential predictive markers of response (e.g., cytogenetics, FISH, Ki67, mutations in NRAS and KRAS) in bone marrow biopsy and/or aspirate samples, and soluble cytokine levels (e.g., VEGF, IL-6, IGF1) in plasma.

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

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.

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.

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

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

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

White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fasted state

Afuresertib GC - Fasted State

White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fasted state

Afuresertib HPMC capsule - Fasted State

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

Afuresertib ECT - Fasted State

White opaque hard gelatin capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib GC administered in fed state

Afuresertib GC - Fed State

White opaque HPMC capsule containing afuresertib 25 mg. Subjects will receive single oral dose of afuresertib HPMC capsule administered in fed state

Afuresertib HPMC capsule - Fed State

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

Afuresertib ECT - Fed State

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.

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

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

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)

AEs will be collected from the start of Study Treatment and until the Follow-up contact

Hematology, clinical chemistry and urinalysis parameters will be measured

Triplicate 12-lead ECGs will be collected at Screening; on Day 1 and Day 3 of each Dosing Period; and at Follow-up

Vital sign measurements will include systolic and diastolic blood pressure and pulse rate

The potential relationship between plasma PK and pharmacodynamic biomarker changes (pAKT) of each formulation will be evaluated

Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

One of two dose combination levels (GSK1120212+GSK2110183) based on data from Part 1 of the trial

Maximum tolerated dose of GSK1120212 as determined in prior single-agent trials

Maximum tolerated dose (MTD) as determined in ongoing single agent trial PKB115340

GSK1120212

The purpose of this study is to determine whether the MEK inhibitor and the AKT inhibitor can be given in combination and if the combination is effective treatment for patients with solid tumors, including breast cancer and endometrial cancer, and for patients with multiple myeloma.

This is an open-label, two part, Phase I/II study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the MEK inhibitor GSK1120212 administered in combination with the AKT inhibitor GSK2110183 in subjects with solid tumors and multiple myeloma.

In Part 1, the safety and tolerability of a range of doses for GSK1120212 and GSK2110183 dosed in combination will be investigated; pharmacokinetics will also be analyzed to determine whether there is a drug-drug interaction between GSK1120212 and GSK2110183 when dosed in combination.

The second part of the study will focus on evaluation of the clinical efficacy of the combination as well as the pharmacodynamic response in subjects with proteasome-refractory multiple myeloma (Part 2A) or solid tumors, putatively endometrial and triple negative breast cancer (Part 2B).

A Study of the Safety and Activity of the MEK Inhibitor Given Together With the AKT Inhibitor to Patients With Multiple Myeloma or Solid Tumor Cancers

An Open-Label, Two Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212 in Combination With the AKT Inhibitor GSK2110183 in Subjects With Solid Tumors and Multiple Myeloma

Adverse events, serious adverse events, dose reductions or delays, withdrawals due to toxicities and changes in laboratory values and vital signs

Defined as stringent complete response, complete response, very good partial response, or partial response, using the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma

Defined as confirmed complete response or confirmed partial response rate, using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1

Parameters include: AUC(0-tau), Ctau, Cmax, and tmax

Progression-free survival (PFS) is defined as the interval between date of randomization and the earliest date of disease progression or death due to any cause; duration of response is defined as the time from first documented evidence of response until time of first documented disease progression; biomarkers in the PI3K/AKT and MAPK pathways, eg pS6RP, pAKT, p-ERK, pRAS40, as measured in bone marrow aspirates/biopsies.

PFS is defined as the interval between date of randomization and the earliest date of disease progression or death due to any cause; duration of response is defined as the time from first documented evidence of complete or partial response until time of first documented disease progression or death due to any cause; biomarkers in the PI3K/AKT and MAPK pathways, eg phosphS6RP, p-ERK, pPRAS40, pAKT measured in tumor tissue.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib	NCT02040480	Cancer	GSK2110183 Gela... GSK2110183 IR T...	18 Years - 40 Years	GlaxoSmithKline
Ph 1b Study to Evaluate GSK2110183 in Combination With Bortezomib and Dexamethasone in Subjects With Multiple Myeloma	NCT01428492	Multiple Myelom...	GSK2110183 Bortezomib Dexamethasone	18 Years -	Novartis
Continuation Study of the Oral AKT Inhibitor GSK2110183	NCT01531894	Cancer	GSK2110183 (afu...	18 Years - 80 Years	Novartis
A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma	NCT01445587	Cancer	Part 1; Cohort ... Part 1; Cohort ... Part 2; Stage 1 Part 2, Stage 2	18 Years -	GlaxoSmithKline
A Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma	NCT01445587	Cancer	Part 1; Cohort ... Part 1; Cohort ... Part 2; Stage 1 Part 2, Stage 2	18 Years -	GlaxoSmithKline
Bioavailability and Food Effect of the Original Gelatin Formulation and Two New Formulations of Afuresertib in Normal Healthy Volunteers	NCT01827644	Cancer	Afuresertib GC ... Afuresertib HPM... Afuresertib ECT... Afuresertib GC ... Afuresertib HPM... Afuresertib ECT...	18 Years - 40 Years	GlaxoSmithKline
Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib	NCT02040480	Cancer	GSK2110183 Gela... GSK2110183 IR T...	18 Years - 40 Years	GlaxoSmithKline
Bioavailability and Food Effect of the Original Gelatin Formulation and Two New Formulations of Afuresertib in Normal Healthy Volunteers	NCT01827644	Cancer	Afuresertib GC ... Afuresertib HPM... Afuresertib ECT... Afuresertib GC ... Afuresertib HPM... Afuresertib ECT...	18 Years - 40 Years	GlaxoSmithKline
A Study of the Safety and Activity of the MEK Inhibitor Given Together With the AKT Inhibitor to Patients With Multiple Myeloma or Solid Tumor Cancers	NCT01476137	Cancer	GSK1120212 GSK2110183	18 Years -	GlaxoSmithKline
Bioavailability and Food Effect Study of Gelatin Formulation and Immediate Release Tablet Formulation of Afuresertib	NCT02040480	Cancer	GSK2110183 Gela... GSK2110183 IR T...	18 Years - 40 Years	GlaxoSmithKline

Spots Global Cancer Trial Database for gsk2110183

Every month we try and update this database with for gsk2110183 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for gsk2110183

Every month we try and update this database with for gsk2110183 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for gsk2110183 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.