Ignite Creation Date:
2024-05-05 @ 6:33 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00504790
Status:
COMPLETED
Last Update Posted:
2018-07-12
First Post:
2007-07-18
Brief Title:
Phase I Study to Assess the Safety Pharmacokinetics Pharmacodynamics of GSK923295 in Subjects w Refractory Cancer
Sponsor:
GlaxoSmithKline
Organization:
GlaxoSmithKline
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2018-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a Phase I open-label first time in human study of GSK923295 in adult subjects with cancers that do not respond to standard therapy This study will be conducted in two stages a dose-escalation stage Stage 1 and an expansion cohort stage Stage 2
Detailed Description:
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 eg 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 endpoints used to assess the objective measures are
Primary
Adverse events AE and changes from baseline in vital signs clinical laboratory parameters and electrocardiography ECG assessments will be evaluated to assess safety profile
Secondary
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 AUC0- AUC0-t Cmax tmax and t12 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-Hodgkins lymphoma
National Cancer Institute - Working Group NCI-WG Guidelines for chronic lymphocytic leukaemia
Exploratory PKPD 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 ie 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-Hodgkins lymphoma and chronic lymphocytic leukemia can also be enrolled
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 eg 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 endpoints used to assess the objective measures are
Primary
Adverse events AE and changes from baseline in vital signs clinical laboratory parameters and electrocardiography ECG assessments will be evaluated to assess safety profile
Secondary
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 AUC0- AUC0-t Cmax tmax and t12 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-Hodgkins lymphoma
National Cancer Institute - Working Group NCI-WG Guidelines for chronic lymphocytic leukaemia
Exploratory PKPD 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 ie 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-Hodgkins lymphoma and chronic lymphocytic leukemia can also be enrolled
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None