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Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy (ImPACCT)

Primary Purpose

Colonic Neoplasms

Status

Terminated

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

Imatinib

About this trial

This is an interventional treatment trial for Colonic Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Meander Medical Center
Diakonessenhuis
University Medical Center Utrecht

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intervention

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen

Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration

Change in plasma CEA-concentrations

Change in plasma levels of circulating tumor DNA

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.

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).

Full Information

NCT ID

NCT02685046

First Posted

February 9, 2016

Last Updated

October 9, 2019

Sponsor

UMC Utrecht

Collaborators

Meander Medical Center, Erasmus Medical Center, Hubrecht Institute

1. Study Identification

Unique Protocol Identification Number

NCT02685046

Brief Title

Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy

Acronym

ImPACCT

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

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Terminated

Why Stopped

Low accrual rate

Study Start Date

April 2016 (undefined)

Primary Completion Date

September 1, 2019 (Actual)

Study Completion Date

September 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

UMC Utrecht

Collaborators

Meander Medical Center, Erasmus Medical Center, Hubrecht Institute

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colonic Neoplasms

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Intervention

Arm Type

Experimental

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Imatinib

Other Intervention Name(s)

Gleevec, STI571

Intervention Description

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 Measure Information:

Title

Effects of treatment on the mesenchymal gene expression profile

Description

Time Frame

period from diagnostic colonoscopy until surgical resection (~5 weeks)

Secondary Outcome Measure Information:

Title

Extent of targeted inhibition of PDGFR and KIT phosphorylation in cancer cells

Description

Time Frame

period from diagnostic colonoscopy until surgical resection (~5 weeks)

Title

Correlation between plasma imatinib trough levels on day 14 and intratumoural concentration of imatinib in the resection specimen

Time Frame

at time of surgery

Title

Correlation between the extent of PDGFR and cKIT inhibition and systemic and intratumoural imatinib and CGP74588 concentration

Time Frame

at time of surgery

Title

Change in plasma CEA-concentrations

Time Frame

period between diagnostic colonoscopy until surgical resection (~5 weeks)

Title

Change in plasma levels of circulating tumor DNA

Time Frame

period between diagnostic colonoscopy until surgical resection (~5 weeks)

Title

Effects of imatinib on the ability of cancer cells to form in vitro 3D cell cultures (organoids)

Description

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.

Time Frame

at time of surgery

Title

Number of participants with treatment-related adverse events as assessed by CTCAEv4.02

Description

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).

Time Frame

from start of treatment until 2 weeks after last dose imatinib

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

I HM Borel Rinkes, MD, PhD

Organizational Affiliation

UMC Utrecht

Official's Role

Principal Investigator

Facility Information:

Facility Name

Meander Medical Center

City

Amersfoort

State/Province

Utrecht

ZIP/Postal Code

3813TZ

Country

Netherlands

Facility Name

Diakonessenhuis

City

Utrecht

ZIP/Postal Code

3582KE

Country

Netherlands

Facility Name

University Medical Center Utrecht

City

Utrecht

ZIP/Postal Code

3584CX

Country

Netherlands

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

28424071

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.

Results Reference

derived

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Imatinib as Pre-operative Anti-Colon Cancer Targeted Therapy

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