Clinical Trials /

Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma

NCT03896113

Description:

Indoleamine 2,3 dioxygenase 1 (IDO 1) is the major enzyme catabolising the Tryptophan outside the liver. It has been shown that its plays a important role in generating a immunosuppressive micro-environment in tumors. IDO expression has been shown by Hennequart et al. to be driven by Cyclooxygenase-2 (COX-2) expression. The investigator's team also shown that anti-COX2, celecoxib, can in a xenograft models of ovarian cancer decrease IDO1 expression and result in an infiltration of the tumor by T cells. The investigator proposed then to conduct a proof of concept study to evaluate the effect of pre-operative short administration of Celecoxib on IDO expression and Immune cells tumors infiltration, in patients with endometrial cancer. Indeed, this tumor type is well known to express frequently a high level of IDO.

Related Conditions:
  • Endometrioid Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT03896113

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma
  • Official Title: Influence of the Celecoxib Administration Before Surgery for Endometrial Cancer on Indoleamine 2,3-dioxygenase 1 (IDO1) Tumor Expression and Immune Cells Tumor's Infiltration

Clinical Trial IDs

  • ORG STUDY ID: LUC19-001
  • NCT ID: NCT03896113

Conditions

  • Endometrium Cancer

Interventions

DrugSynonymsArms
Celecoxib 200mg capsuleCyclooxygenase-2 (COX-2) inhibitorCelecoxib

Purpose

Indoleamine 2,3 dioxygenase 1 (IDO 1) is the major enzyme catabolising the Tryptophan outside the liver. It has been shown that its plays a important role in generating a immunosuppressive micro-environment in tumors. IDO expression has been shown by Hennequart et al. to be driven by Cyclooxygenase-2 (COX-2) expression. The investigator's team also shown that anti-COX2, celecoxib, can in a xenograft models of ovarian cancer decrease IDO1 expression and result in an infiltration of the tumor by T cells. The investigator proposed then to conduct a proof of concept study to evaluate the effect of pre-operative short administration of Celecoxib on IDO expression and Immune cells tumors infiltration, in patients with endometrial cancer. Indeed, this tumor type is well known to express frequently a high level of IDO.

Detailed Description

      Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that regulates immune responses by
      degrading tryptophan, which is required for efficient T-cell activation. IDO1 expression is
      limited in normal tissues but is induced by IFN-gamma in inflammatory tissues, to prevent
      excessive T-cell activity. The investigator's collaborators previously reported that IDO1 is
      expressed in many human tumours, and that pharmacological inhibition of IDO1 leads to immune
      rejection of IDO1+ mouse tumours. Based on these results, IDO1 inhibitors are now in clinical
      development. A first inhibitor, Epacadostat, showed encouraging results combined with anti-
      Programmed Cell Death -1 (PD-1) antibodies. Tumoural expression of IDO1 can be induced by
      IFN-gamma, which is produced by tumour-infiltrating lymphocytes (TIL), and represents a
      mechanism of adaptive immune resistance. However, other tumours express IDO1 in the absence
      of TIL and Interferon-gamma (INF gamma). This seems to be particularly frequent in
      endometrial carcinoma. This constitutive IDO1 expression prevents T-cell infiltration and
      represents a mechanism of intrinsic immune resistance. The investigator's collaborators
      recently showed that constitutive tumoural expression of IDO1 was triggered by
      cyclooxygenase-2 (COX-2) and mediated by autocrine prostaglandin-E2 (PGE2) signaling via the
      Protein Kinase C (PKC) and phosphoinositide 3-kinase (PI3K) pathways. Constitutive IDO1
      expression was reduced by COX-2 inhibitors in vitro. Celecoxib is a well-known and widely
      used anti-inflammatory drug. It is a specific inhibitor of COX-2. In vivo, celecoxib induced
      immune rejection of IDO1-expressing human tumour xenografts, while reducing IDO1 expression
      and promoting T-cell infiltration. These preclinical results suggest that COX-2 inhibition in
      patients carrying tumours expressing IDO1 constitutively will decrease IDO1 expression,
      increase T-cell infiltration and might increase responsiveness to anti-PD-1/ Programmed Cell
      Death Ligand-1(PD-L1) therapy and thereby exert enhanced anti-tumour activity. The
      investigators wish to obtain clinical evidence that celecoxib can induce these first two
      effects

Trial Arms

NameTypeDescriptionInterventions
CelecoxibExperimentalPatients with confirmed primary endometrioid adenocarcinoma eligible for first line curative surgery will receive celecoxib 400 mg twice a day, for 15 days before the curative surgery for their endometrial cancer. The patients will undergo an endometrial biopsy at the inclusion and during the surgery.
  • Celecoxib 200mg capsule

Eligibility Criteria

        Key Inclusion Criteria:

          -  Women > 18 years of age.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

          -  Adequate renal, hepatic and haematologic functions as defined by laboratory
             parameters.

          -  Agrees to undergo additional endometrial biopsies for scientific purposes.

        Key Exclusion Criteria:

          -  Known hypersensitivity or intolerance to celecoxib

          -  Active, known or suspected autoimmune disease. Vitiligo, type I diabetes mellitus,
             residual hypothyroidism controlled by hormone substitution therapy, psoriasis not
             requiring systemic treatment, or conditions not expected to recur in the absence of an
             external trigger are allowed.

          -  Positive hepatitis B or C, HIV, and pregnancy tests.

          -  Immunosuppressive treatment
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Reduction of tumoural cells expression IDO after celecoxib treatment. If more than 10% of all the tumoural cells have a staining for IDO, the tumour is considered as IDO (+), if less than 10%.
Time Frame:after 15 days of celecoxib administration
Safety Issue:
Description:Reduction of Tumoral IDO expression after Celecoxib treatment by immunohistochemistry, digital identification of the cells and phenotype and computer count of IDO positive cells inside de tumour (then total number compared before and after the treatment). If more than 10% of all the tumoural cells have a staining for IDO, the tumour is considered as IDO (+), if less than 10%, it is considered as (-). Based on animal models, the treatment with celecoxib should decreases IDO expression in tumoural cells, allowing an immune cells tumoural's infiltration.

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Event Version 4.0 (CTCAE v4.0).
Time Frame:from the first intake of the celecoxib to one day after the surgery
Safety Issue:
Description:Assessment and scaling of adverse events according to CTCAE v4.0, Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to Adverse Event.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Last Updated

January 10, 2020