An Open-Label, Single Arm, Phase Ib/II Study of GSK2110183 in Subjects With Proteasome Inhibitor Refractory Multiple Myeloma
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.,
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Evaluate the safety and tolerability of GSK2110183 in subjects with proteasome inhibitor refractory MM.
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.
Subjects will continue on the study from the date of randomization until the date of the first documented progression or when the subjects meet one of the Treatment Discontinuation Criteria and may be assessed on average up to 48 months.
GSK Clinical Trials
United States: Food and Drug Administration