A Phase I, Open-Label, Dose-Escalation, First Time in Human Study to Evaluate the Safety Profile, Pharmacokinetics, and Pharmacodynamics of GSK923295 in Subjects With Refractory Cancers
Centromere-associated protein E (CENP-E) is a protein that is required for correct
chromosomal alignment in mitosis. Loss of CENP-E activity, due to microinjection of
antibodies, ablation of gene expression with siRNA or antisense oligonucleotides, or
inhibition of enzymatic activity by small molecule inhibitors, causes aberrant cell cycle
arrest in mitosis, characterized by a bipolar mitotic spindle with misaligned chromosomes.
Studies with small molecule inhibitors have demonstrated that this aberrant cell cycle
arrest can result in apoptosis and cell death. CENP-E has been shown to be abundantly
expressed in a variety of human tumors. GSK923295 is a potent and selective CENP-E inhibitor
which has demonstrated potent and broad spectrum antitumor activity against solid and
hematologic malignancies in vitro. GSK923295 is intended for use either as a monotherapy or
in combination with existing anti-cancer therapies.
A drug targeting CENP-E may prove as efficacious as the taxanes and vinca alkaloids, without
the potential for neurotoxicity or other side-effects associated with interference of
tubulin function in non-dividing cells. Similar to many other anti-proliferative drugs,
CENP-E inhibitors are expected to have manageable dose-limiting toxicities resulting from
action on normal proliferating tissues (e.g., myelosuppression and gastrointestinal
epithelial cell damage). The opportunity for inhibitors of CENP-E lies in the potential for
broad efficacy. The absence of broad clinical experience with anti-mitotic cancer therapies
acting on targets other than tubulin complicates prediction of additional benefits, beyond
the lack of neurotoxicity that might accrue from a drug targeting CENPE.
The purpose of this Phase I, first time in human (FTIH) study in subjects with refractory
cancers is to determine the maximally tolerated dose (MTD) (or recommended dose based on
available safety, pharmacokinetic (PK) and response data), dose-limiting toxicities (DLTs),
PK, pharmacodynamics (PD), and preliminary clinical activity of GSK923295, an inhibitor of
The primary objectives in Stage 1 (Dose Escalation) are:
• To determine the MTD (or recommended dose based on available safety, PK, and response
data), DLTs, safety, and PK of GSK923295 administered to subjects with advanced, refractory
The primary objectives in Stage 2 (Expansion Cohort) are:
• To evaluate the safety and PK of GSK923295 at the MTD (or recommended dose based on
available safety, PK, and response data) administered to subjects with advanced, refractory
Secondary Objectives in the study are:
- To determine the clinical activity of GSK923295 administered to subjects with advanced,
- To evaluate the effect of GSK923295 on biomarkers in normal host tissue (Stage 1 and 2)
and tumor (Stage 2, optional in Stage 1) and the effect of GSK923295 on tumor
metabolism with FDG-PET imaging (Stage 2, optional in Stage 1).
- Explore associations between biochemical and genetic characteristics of baseline
archival tumor specimens (Stage 1 and Stage 2), biopsy-accessible tumor specimens
(Stage 2), and anti-tumor response.
- Explore pharmacogenomic associations between genetic variants in drug metabolizing and
drug transport genes and PK, safety, and efficacy of GSK923295.
The primary and secondary endpoint(s) used to assess the objective measures are:
• Adverse events (AE) and changes from baseline in vital signs, clinical laboratory
parameters, and electrocardiography (ECG) assessments will be evaluated to assess safety
- The MTD (or recommended dose based on available safety, PK, and response data) where no
more than 1 of 6 subjects has a DLT in the first treatment cycle.
- PK parameters CL, Vdss, AUC(0-∞), AUC(0-t), Cmax, tmax, and t1/2 (Stage 1) and develop
a PK model for GSK923295 (Stage 1 and 2).
- Anti-tumor activity measurements will be obtained at baseline and after every second
cycle according to the following:
- Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines for solid tumors (for
solid tumors and non-Hodgkin's lymphoma).
- National Cancer Institute - Working Group (NCI-WG) Guidelines for chronic lymphocytic
- Exploratory PK/PD modeling of safety and response data.
- Changes in biomarkers of cell proliferation and cell death or imaging endpoints.
- Biomarker profiles in archival tumor specimens and their correlation with clinical
- Genetic polymorphisms in key enzymes involved in the metabolism and disposition of
GSK923295 and correlations with pharmacokinetic, safety, and response (pharmacodynamic)
The study will consist of two stages. Stage 1 consists of a dose escalation stage to
determine the MTD (or recommended dose based on available safety, PK and response data)
using an accelerated titration scheme combined with standard dose escalation methods.
GSK923295 will be administered intravenously over one hour, once weekly for 3 consecutive
weeks (i.e., Day 1, 8, and 15) with treatment cycles repeated every 4 weeks (each cycle = 28
days). During Stage 1, safety, pharmacokinetics, pharmacodynamics, and clinical activity
will be assessed. Tumor biopsies and PET imaging are optional in Stage 1 subjects. The MTD
(or recommended dose based on available safety, PK and response data) will be defined as the
dose of GSK923295 at which no more than 1 of 6 subjects experiences a DLT in the first
treatment cycle. Eighteen subjects are anticipated to participate in Stage 1 of the study.
In Stage 2, 15-20 additional subjects will be enrolled at the MTD (or recommended dose based
on available safety, PK and response data) dose to further evaluate the safety of GSK923295.
In Stage 2, PK samples (using a sparse PK sampling scheme for population PK analyses), PET
imaging, and tumor biopsies will be obtained. Clinical activity will be assessed. Subjects
(Stage 1 and Stage 2) will remain on study until they meet the criteria for treatment
discontinuation described in the protocol. It is anticipated that 33-38 subjects will
participate in the study (18 in Stage 1 and 15-20 in Stage 2. During Stage 1 and Stage 2,
subjects with histologically confirmed advanced refractory solid tumors will be enrolled. In
Stage 2, subjects with refractory non-Hodgkin's lymphoma and chronic lymphocytic leukemia
can also be enrolled.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety: - physical exam
at screen & Day(D) 1 of each cycle and follow-up(F/U)
GSK Clinical Trials
United States: Food and Drug Administration
|GSK Investigational Site||Bakersfield, California 93309|
|GSK Investigational Site||Green Bay, Wisconsin 54301|
|GSK Investigational Site||Royal Oak, Michigan 48073|