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

Summary

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.

Conditions

• Cancer

Interventions

DRUG

Part 1; Cohort 1

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.

DRUG

Part 1; Cohort 2

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.

DRUG

Part 2; Stage 1

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.

DRUG

Part 2, Stage 2

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

Sponsors & Collaborators

• GlaxoSmithKline

  lead INDUSTRY

Principal Investigators

• GSK Clinical Trials · GlaxoSmithKline

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2011-11-30

Primary Completion

2011-11-30

Completion

2011-11-30

Countries

• Australia

Study Locations