Clinical trial NCT02274753: Personalizing Colorectal Cancer Medicine (ImmuCol2)
Official title: Personalizing Colorectal Cancer Medicine: an Integrative Approach for the Identification of Prognostic Parameter Combinations at the Time of Surgery and During the Follow-up
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Colon Cancer
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2014-10-24
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adult patient with newly diagnosed colon cancer.

Brief summary: Colorectal cancers are the leading cancers for both sexes combined. They represent 15-20% of all cancers. This cancer has a severe prognosis, the survival rate at 5 years is around 55% and in France it is estimated, all colorectal cancers are responsible for an annual mortality of 15,000 patients. The prognosis of colon cancer knows no significant improvement.

The treatment of colon cancer is surgical. It is intended for removal of colonic segment bearing the tumor with margins of healthy colon. The therapeutic attitude following the surgery is essentially driven by histopathology of the tumor. Adjuvant chemotherapy for all patients with localized stage II provides no benefit because the effectiveness of chemotherapy is limited and vulnerable to systemic toxicity. However, nearly 30% of patients with stage II disease will have a recurrence / metastasis. These patients could benefit from adjuvant chemotherapy.

Intense research efforts have been made to identify markers predictive of relapse. Over thirty biological markers (eg. Mutations, deletions, chromosomal instability, ...) were highlighted. None of them has so far sufficient prognostic value (independent of TNM) to justify routine application in clinical practice in order to adapt the treatment of patients.

The identification of new prognostic markers is a major issue for colorectal cancer. We showed that the intratumoral density memory T lymphocytes (CD45RO) and cytotoxic (CD8) strongly influenced the clinical outcome of patients. We have developed and validated a "immunoscore" technique intratumoral immune quantification and creates a platform to facilitate the clinical immuno transfer.

We are currently conducting a large international retrospective study (22 centers,\> 9000 patients) with promotion of cancer immunotherapy Company (SITC) to validate the method "immunoscore." At the same time, we are conducting a prospective multicenter study "ImmuCol" (National PHRC) to validate the prognostic value of "immunoscore" in colorectal cancer stage I-IV. The goal of inclusion has been achieved, as 420 patients were included for 18 months. Clinical follow-up will be 3 years after surgery.

The program ImmuCol2 research takes advantage of the ImmuCol study to extend the investigation beyond the immunoscore to define the combination of interest, prognostic and theranostic parameters at diagnosis and during the clinical course patients with an objective of personalized medicine.

Detailed description: The project aims:

(i) to combine at time of diagnosis the immunoscore with parameters related to the patient, its tumor and the associated microenvironment (ii) to detect events occurring during the follow up period that could modify the initial prognosis and lead to a repositioning of the patient, to move towards a dynamic personalized medicine.

(iii) to explore the Theranostic aspect of the parameters monitored at the time of diagnosis for patients with colonic cancers treated with adjuvant chemotherapy.

To this end we will investigate:

* Tumor's features:

  - We will determine the microsatellite instability status and search for mutations of 46 genes (ABL1, AKT1, ALK, APC, ATM, BRAF, CCDH1, CDKN2A, CSF1R, CTNNB, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, NOTCH1, NPM1, NRAS, PDGFRA, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, STK11, TP53, VHL) by next generation sequencing (NGS).
* Tumor immune microenvironment features:

  - 24 immune related genes, 24 miRNA and co-inihibitory molecules (PD1, PD1-L, LAG-3, TIM3, CTLA-4) will be explored on tumor samples.
* Systemic disorders:

  * Autoimmunity, allergy or inflammatory diseases will be sought with a dedicated questionnaire filled out by the patient and a serum examination for the screening of immune disorders at the time of diagnosis and during the survey.
  * The nutritional status (% of weight loss) and the deficiencies in vitamins, folic acid, trace elements and thyroid hormones that synergise with immune cells will be determined at the time of diagnosis.
* Psychological status:

  - The impact of the psychological profile of the patient will be investigated with a dedicated questionnaire, given at the time of diagnosis and every six months.
* Data mining to achieve a dynamic personalized medicine:

The integration and statistical analysis of heterogeneous data types (clinical and different experimental data) will be performed using with tranSMART, an open source platform and with bioinformatic tools (TMEdb, ClueGO, CluePedia, Genesis) developed by participant teams.

Eligibility criteria: Inclusion Criteria:

* Adult patient with newly diagnosed colon cancer
* Patient with signed informed consent
* Patient follow-up during the first three years made in the recruiting center

Exclusion Criteria:

* Adjuvant treatment (chemotherapy) started at the time of inclusion

Primary outcomes:
measure: Relapse in relation with the immunoscore determined on a tumor section and criteria defined in the monitoring of patients
timeFrame: 3 years
Secondary outcomes:
measure: Relapse in relation with the immune component cancers beyond immunoscore
timeFrame: Every 3 months during 2 years and every 6 months during the third year
measure: Relapse in relation with the immunoscore on biopsies
timeFrame: Every 3 months during 2 years and every 6 months during the third year
Other outcomes:
Locations:
city: Besançon
country: France
facility: Hopital de Besançon (CHU)
city: Bobigny
country: France
facility: Hopital Avicenne
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Bordeaux
country: France
facility: Institut Bergonié Bordeaux
city: Clichy
country: France
facility: Hopital Beaujon
city: Dijon
country: France
facility: Hopital de Dijon (CHU)
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou (HEGP)
city: Poitiers
country: France
facility: Hopital de Poitiers (CHU)
city: Rouen
country: France
facility: Hopital Charles Nicolle (CHU)
Study officials:
affiliation: AP-HP; Paris Descartes University
name: Franck Pages, Professor (MD-PHD)
role: PRINCIPAL_INVESTIGATOR
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