Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy

Phase 2

Terminated

• Conditions: Colonic Neoplasms
• Interventions: Drug: Imatinib

• Registration Number: NCT02685046
• Lead Sponsor: UMC Utrecht

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2016-02-09
• Study First Submitted QC: 2016-02-12
• Study First Posted: 2016-02-18
• Study Start: 2016-04
• Primary Completion: 2019-09-01
• Study Completion: 2019-09-01
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-09
• Last Update Posted: 2019-10-14

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 5

Inclusion Criteria

1. Male or female aged ≥18 years

2. Histologically proven adenocarcinoma of the colon;

3. Completed cancer staging with CT-abdomen and CT-thorax/X-thorax according to hospital's standard of care;

4. Confirmed eligibility for surgery with curative intent as deemed by the hospital's multidisciplinary board (MDB) review;

5. 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);

6. Minimum of four properly stored pre-treatment biopsies for gene expression analysis/ELISA;

7. WHO performance status 0 or 1;

8. 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

9. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests;

10. Written informed consent.

Exclusion Criteria

1. The presence of synchronous distant metastases;
2. Current hospital standard of care dictates that subject should undergo any neoadjuvant therapy;
3. 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;
4. 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;
5. Known HIV or Hepatitis B/C infection;
6. Known symptomatic congestive heart failure;
7. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intervention	Imatinib	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.

Primary Outcome Measures

Name	Time	Method
Effects of treatment on the mesenchymal gene expression profile	period from diagnostic colonoscopy until surgical resection (~5 weeks)	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.

Secondary Outcome Measures

Name	Time	Method
Extent of targeted inhibition of PDGFR and KIT phosphorylation in cancer cells	period from diagnostic colonoscopy until surgical resection (~5 weeks)	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.
Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen	at time of surgery
Change in plasma levels of circulating tumor DNA	period between diagnostic colonoscopy until surgical resection (~5 weeks)
Number of participants with treatment-related adverse events as assessed by CTCAEv4.02	from start of treatment until 2 weeks after last dose imatinib	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).
Change in plasma CEA-concentrations	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)	at time of surgery	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.
Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration	at time of surgery

Trial Locations

Locations (3)

Diakonessenhuis; 🇳🇱 Utrecht, Netherlands

Meander Medical Center; 🇳🇱 Amersfoort, Utrecht, Netherlands

University Medical Center Utrecht; 🇳🇱 Utrecht, Netherlands