Phase I Study to Assess the Safety, Pharmacokinetics, & Pharmacodynamics of GSK923295 in Subjects w/ Refractory Cancer
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||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|
- Safety: - physical exam [ Time Frame: at screen & Day(D) 1 of each cycle and follow-up(F/U) ]
- - vital signs and lab tests [ Time Frame: at screen & D1, 8, 15, & 22 for each cycle & F/U ]
- - ECGs [ Time Frame: at screen and D1, 8 & 15 for each cycle & F/U ]
- continuous monitoring of adverse events [ Time Frame: each visit ]
- Plasma samples of GSK923295 taken at: [ Time Frame: - Day 1 & 15 (Cycle 1) for Stage 1 ]used to measure levels of the drug in blood over time
- Plasma samples of GSK923295 taken at: [ Time Frame: - Day 1 of each cycle for Stage 2 ]used to monitor levels of the drug in blood
|Actual Study Start Date:||June 25, 2007|
|Study Completion Date:||May 8, 2012|
|Primary Completion Date:||May 8, 2012 (Final data collection date for primary outcome measure)|
anti-mitotic compound under study
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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 CENP-E.
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 malignancies.
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 malignancies.
Secondary Objectives in the study are:
- To determine the clinical activity of GSK923295 administered to subjects with advanced, refractory malignancies.
- 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 profile.
- 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 leukaemia.
- 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 activity.
- Genetic polymorphisms in key enzymes involved in the metabolism and disposition of GSK923295 and correlations with pharmacokinetic, safety, and response (pharmacodynamic) data.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00504790
|United States, California|
|GSK Investigational Site|
|Duarte, California, United States, 91010|
|United States, Michigan|
|GSK Investigational Site|
|Detroit, Michigan, United States, 48201|
|United States, Wisconsin|
|GSK Investigational Site|
|Madison, Wisconsin, United States, 53792-5666|
|Study Director:||GSK Clinical Trials||GlaxoSmithKline|