Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Celecoxib

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Enzyme Inhibitors

Patients 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.

Patient confirmed with endometrial cancer will received twice daily 200 mg Celecoxib, 15 days before the surgery.

Celecoxib 200mg capsule

Mathieu Luyckx, MD

Jean-Luc Squifflet, PhD

Ignace Vergote, PhD

An Coosemans, PhD

Benoit van den Eynde, PhD

Nicolas Van Baeren, PhD

Jean-François Baurain, PhD

Pierre van der Bruggen, PhD

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.

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

Open label, proof of concept phase II study. One arm, no placebo: All the patient will received the treatment and biopsies before and after the treatment will be compared regarding Indoleamine 2,3-dioxygenase 1 (IDO-1) expression and Immune T cells infiltration of the tumour

Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma

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

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.

Observed the modification of the T cell tumoral's infiltration after the celecoxib treatment by immunohistochemistry, digital identification of the cells and phenotype and computer count of the different T cells population inside de tumour (then total number compared before and after the treatment). The number of CD4 and CD8 T cells will be counted before and after the treatment and the median of all the sample before and after the treatment will be compared to assess if there is a significant difference of total number of T cells before and after the treatment. Unit= nombre of CD4 and CD8 T Cells. Based on animal model, the investigators expect to have a significant increase of T cells infiltration after the celecoxib treatment

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.

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma	NCT03896113	Endometrium Can...	Celecoxib 200mg...	18 Years - 99 Years	Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Neoadjuvant Celecoxib in Newly Diagnosed Patients With Endometrial Carcinoma	NCT03896113	Endometrium Can...	Celecoxib 200mg...	18 Years - 99 Years	Cliniques universitaires Saint-Luc- Université Catholique de Louvain

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