Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy

Study Overview
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Brief Summary
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In this proof-of-concept trial the investigators will study the effects of imatinib treatment on the biology of mesenchymal-type colon cancers.

Detailed Description
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Tumor biopsies from patients with newly diagnosed colon cancer will be pre-screened with an RT-qPCR test to identify tumors of the mesenchymal subtype. Patients with mesenchymal-type tumors that meet the in- and exclusion criteria will be treated with imatinib during the window period that normally precedes surgery. Immediately following tumor resection, biopsies will be taken from the surgical specimen. Gene and protein expression of the pre- and post-treatments biopsies will be compared to assess the effects of imatinib therapy on PDGFR- and cKIT-signalling and on the mesenchymal gene expression profile.

Official Title
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Targeted Therapy With Imatinib for Treatment of Poor Prognosis Mesenchymal-type Resectable Colon Cancer: a Proof-of-concept Study in the Preoperative Window Period.

Conditions
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Colonic Neoplasms

Intervention / Treatment
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* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥18 years Histologically proven adenocarcinoma of the colon; Completed cancer staging with CT-abdomen and CT-thorax/X-thorax according to hospital's standard of care; Confirmed eligibility for surgery with curative intent as deemed by the hospital's multidisciplinary board (MDB) review; An intratumoural gene expression profile of PDGFR-α, PDGFR-β, PDGF-C and KIT, indicative of the mesenchymal phenotype, according to our diagnostic RT-qPCR test (i.e. more than 50% chance of having the mesenchymal phenotype); Minimum of four properly stored pre-treatment biopsies for gene expression analysis/ELISA; WHO performance status 0 or 1; Adequate haematology status and organ function, defined as: Normal creatinine clearance (≥60 ml/min (MRDR)) ALAT within 2.5x upper limit of normal (ULN) PT-INR < 1.5 Leukocytes > 1,5*10^9/L; Hb > 6.0 mmol/L; platelets > 100*10^9/L Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests; Written informed consent. Exclusion Criteria: The presence of synchronous distant metastases; Current hospital standard of care dictates that subject 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; Women who are pregnant, plan to become pregnant or are lactating during the study or for up to 30 days after the last dose of imatinib; Known HIV or Hepatitis B/C infection; Known symptomatic congestive heart failure; Co-morbidity requiring concomitant treatment with drugs that act as strong inducers of CYP3A4 or with drugs with a narrow therapeutic range influenced by imatinib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Subjects will be treated with the medicinal product imatinib, which will be administered orally in tablets of 400mg, once per day, during two weeks prior to tumor resection. | Drug: Imatinib<br>* Subjects will be treated with the medicinal product imatinib, which will be administered orally in tablets of 400mg, once per day, during two weeks prior to tumor resection.<br>* Other names: STI571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of treatment on the mesenchymal gene expression profile | 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. | period from diagnostic colonoscopy until surgical resection ( 5 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extent of targeted inhibition of PDGFR and KIT phosphorylation in cancer cells | 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. | period from diagnostic colonoscopy until surgical resection ( 5 weeks) | 
| Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen |  | at time of surgery | 
| Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration |  | at time of surgery | 
| Change in plasma CEA-concentrations |  | period between diagnostic colonoscopy until surgical resection ( 5 weeks) | 
| Change in plasma levels of circulating tumor DNA |  | period between diagnostic colonoscopy until surgical resection ( 5 weeks) | 
| Effects of imatinib on the ability of cancer cells to form in vitro 3D cell cultures (organoids) | 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. | at time of surgery | 
| Number of participants with treatment-related adverse events as assessed by CTCAEv4.02 | The occurrence, frequency and severity of adverse events during preoperative treatment with imatinib, peroperatively or in the postoperative period (up to 14 days after tumour resection). | from start of treatment until 2 weeks after last dose imatinib |