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.
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.