colon cancer
Conditions
Interventions
Trade Name: Glivec
Product Name: Imatinib
Product Code: ST1571
Pharmaceutical Form: Tablet
Sponsors
University Medical Center Utrecht
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically proven adenocarcinoma of the colon; 2. Confirmed eligibility for surgery with curative intent as deemed by the hospital’s multidisciplinary team (MDT) review; 3. High intratumoural gene expression of PDGFR-a, PDGFR-ß, PDGF-C and KIT according to our diagnostic RT-qPCR test. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 27 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 27
Exclusion criteria
Exclusion criteria: The presence of synchronous distant metastases; Current hospital standard of care dictates that patient should undergo any neoadjuvant therapy; Concurrent participation in another clinical trial using any medicinal product, or participation in such a trial in the period of three months prior to the current trial;
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main objective is to study the effects of targeted PDGFR and cKIT signalling inhibition with imatinib on gene expression profiles of colon tumours with a high chance of having the mesenchymal phenotype. ;Secondary Objective: I. To measure the extent of inhibition of PDGFR- and cKIT-signalling by treatment with imatinib. II. To relate intra-tumoural imatinib pharmacokinetics (PK) to systemic imatinib concentrations. III. To relate the level of inhibition of PDGFR/cKIT signalling and the extent of changes in gene expression to the systemic and intra-tumoural PK of imatinib and its active metabolite CGP74588. IV. To study changes in tumour load during treatment by measuring the concentrations of plasma-CEA and circulating tumour DNA (ctDNA). V. To study the effects of imatinib on organoid-forming potential. VI. To study the effects of imatinib on gene and protein expression in an unbiased fashion. VII. To assess the safety and tolerability of pre-operative imatinib therapy in patients who will undergo bowel surgery for colon cancer. ;Primary end point(s): To assess the extent of change in the mesenchymal phenotype, gene expression arrays will be generated from pre- and post-treatment tissue samples and the expression of genes associated with the poor-prognosis mesenchymal subtype will be compared. ;Timepoint(s) of evaluation of this end point: Primary endpoints will be analysed in one batch after the last's patients last visit. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): I. Measurement of PDGFR and cKIT inhibition by comparison of the fraction of autophosphorylated PDGFR and cKIT pre-treatment versus post-treatment, measured with ELISA on tissue samples derived from diagnostic biopsies and surgery. II. Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen. III. Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration. IV. Alterations in plasma CEA-concentrations and levels of ctDNA before and after treatment. V. The ability to establish organoids from imatinib-treated tumours will be compared with the general success rate of organoid formation from colon tumours at the Hubrecht Institute. If organoids can be established from imatinib-treated tumours, these will be further compared with untreated mesenchymal-type tumour-derived organoids, in terms of clone-forming potential and tumour-forming potential. VI. Analysis of differentially expressed genes in the pre- and post-treatment samples with several pathway recognition and enrichment tools such as Ingenuity, SPEED and GSEA. Changes in gene expression can be validated using qPCR and/or ELISA. VII. The occurrence, frequency and severity of adverse events (AEs) during preoperative treatment with imatinib, peroperatively or in the postoperative period (up to 14 days after tumour resection). ;Timepoint(s) of evaluation of this end point: Occurrence of AEs will be monitored throughout the trial. The remaining analysis will be performed in one batch after the last's patients last visit. | — |
Countries
Netherlands
Contacts
Public ContactInge Ubink
University Medical Center Utrecht
Outcome results
None listed