Clinical trial NCT02685046: Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy
Official title: Targeted Therapy With Imatinib for Treatment of Poor Prognosis Mesenchymal-type Resectable Colon Cancer: a Proof-of-concept Study in the Preoperative Window Period.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colonic Neoplasms
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Meander Medical Center
name: Erasmus Medical Center
name: Hubrecht Institute
First posted: 2016-02-18
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Effects of treatment on the mesenchymal gene expression profile
timeFrame: period from diagnostic colonoscopy until surgical resection (~5 weeks)
Secondary outcomes:
measure: Extent of targeted inhibition of PDGFR and KIT phosphorylation in cancer cells
timeFrame: period from diagnostic colonoscopy until surgical resection (~5 weeks)
measure: Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen
timeFrame: at time of surgery
measure: Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration
timeFrame: at time of surgery
measure: Change in plasma CEA-concentrations
timeFrame: period between diagnostic colonoscopy until surgical resection (~5 weeks)
measure: Change in plasma levels of circulating tumor DNA
timeFrame: period between diagnostic colonoscopy until surgical resection (~5 weeks)
measure: Effects of imatinib on the ability of cancer cells to form in vitro 3D cell cultures (organoids)
timeFrame: at time of surgery
measure: Number of participants with treatment-related adverse events as assessed by CTCAEv4.02
timeFrame: from start of treatment until 2 weeks after last dose imatinib
Other outcomes:
Locations:
city: Amersfoort
country: Netherlands
facility: Meander Medical Center
state: Utrecht
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: I HM Borel Rinkes, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ubink I, Bloemendal HJ, Elias SG, Brink MA, Schwartz MP, Holierhoek YCW, Verheijen PM, Boerman AW, Mathijssen RHJ, de Leng WWJ, de Weger RA, van Grevenstein WMU, Koopman M, Lolkema MP, Kranenburg O, Borel Rinkes IHM. Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT). BMC Cancer. 2017 Apr 19;17(1):282. doi: 10.1186/s12885-017-3264-y.